Resorcinol derivatives

ABSTRACT

The present invention relates to certain resorcinol derivatives and their use as skin lightening agents.

This application claims priority from U.S. provisional application Ser.No. 60/231,623, filed Sep. 11, 2001 which is incorporated by referencein its entirety.

FIELD OF THE INVENTION

The present invention relates to certain resorcinol derivatives andtheir use as skin lightening agents.

BACKGROUND OF THE INVENTION

The terms “lightening agent” and “depigmentation agent” are usedinterchangeably throughout this document.

Skin color in humans arises from a complex series of cellular processesthat are carried out within a unique population of cells calledmelanocytes. Melanocytes are located in the lower part of the epidermis,and their function is to synthesize a pigment, melanin, which protectsthe body from the damaging effects of ultraviolet radiation.

When skin is exposed to ultraviolet radiation, such as that contained insunlight, melanocytes increase their synthesis of melanin. Melanin isdeposited in melanosomes, which are vesicles found within the cell. Themelanosomes are extruded from the cell and carried to the surface of theskin by keratinocytes, which internalize the melanin-containingmelanosomes. The end result is that the visible layers of the skinexhibit a brown color typically known as a “tan”. The darkness of thecolor observed in the skin is proportionate to the amount of melaninsynthesized by melanocytes and transferred to the keratinocytes.

The mechanism by which skin pigmentation is formed, melanogenesis, isparticularly complex and schematically involves the following mainsteps: Tyrosine→L-Dopa→Dopaquinone→Dopachrome→Melanins. The first tworeactions in this series are catalyzed by the enzyme tyrosinase. Theactivity of tyrosinase is promoted by the action of α-melanocytestimulating hormone or UV rays. It is well established that a substancehas a depigmenting effect if it acts directly on the vitality of theepidermal melanocytes where melanogenesis normally occurs and/or if itinterferes with one of the stages in melanin biosynthesis. The activecompounds that are employed in the various methods and compositions ofthis invention inhibit tyrosinase and thus inhibit or decrease melaninbiosynthesis.

There is a strong demand for agents that enable acquired depositionsites, such as spots or freckles, to be restored to a normal skin color.For this purpose, a variety of agents and methods have been developedand put on the market. Examples of such methods are (a) a method whereinvitamin C (L-ascorbic acid) having good reducing ability is administeredorally in large amounts, (b) a method wherein glutathione isadministered parenterally; (c) a method wherein a peroxide, such ashydrogen peroxide, zinc peroxide, sodium peroxide and the like, isadministered: and (d) a method wherein vitamin C or cysteine isadministered topically in the form of an ointment, cream, lotion or thelike. Vitamin C has a problem with respect to stability and becomes sounstable in water-containing systems that they will cause changes inodor and color. Thiol compounds such as glutathione and cysteine do notexhibit a satisfactory depigmental effect since the development of theeffect is very slow.

The substances in widest use at the present time as depigmentors are, inparticular, hydroquinone and its derivatives, particularly its etherssuch as hydroquinone monomethyl ether. These compounds, while effective,are known to produce side effects that can be dangerous. Hydroquinone,use of which is limited to a concentration of 2%, is both irritating andcytotoxic to the melanocyte.

U.S. Pat. No. 4,526,179 refers to certain hydroquinone fatty esters thathave good activity and are less irritating and more stable thanhydroquinone.

Japanese Patent Application No. 27909/86 refers to other hydroquinonederivatives that do not have the drawbacks of hydroquinone but that haverelatively poor efficacy.

U.S. Pat. No. 5,449,518 refers to 2,5-dihydoxyphenyl carboxylic acidderivatives as skin depigmentation agents.

European Patent Application EP 341,664A1 refers to certain resorcinolderivatives as tyrosinase inhibitors and skin depigmentation agents.

PCT International Publication WO 99/15148 refers to certain resorcinolderivatives as tyrosinase inhibitors and skin depigmentation agents.

The use of topical depigmention agents that have good efficacy and areharmless is particularly desirable for treating the following: regionalhyperpigmentation caused by melanocytic hyperactivity, such asidiopathic melasma occurring either during pregnancy (mask of pregnancyor chloasma) or secondary to estrogen-progesterone contraception; localhyperpigmentation caused by benign melanocytic hyperactivity andproliferation such as lentigo senilis or liver spots; accidentalhyperpigmentation such as post-lesional photosensitization and scarring;and certain forms of leukoderma such as vitiligo where, if the injuredskin cannot be repigmented, the residual zones of normal skin aredepigmented to impart a homogeneous white color to the entire skin.

SUMMARY OF INVENTION

The resorcinol derivatives of formula I, which are defined below andused in the various methods and compositions of this invention, areuseful in the treatment of the foregoing dermatological conditions aswell as other dermatological conditions, some of which are referred tolater in this document, for which the subject being treated desires, formedicinal or cosmetic purposes, to lighten or reduce the pigmentation ofthe skin affected by the condition.

The resorcinol derivatives of formula I are also useful for thetreatment of inflammatory disorders such as psoriasis, dermatitis andacne, and for the treatment of dandruff.

The invention thus provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R is a (C₃-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring, whereineither the cycloalkyl ring or cycloalkenyl ring is substituted by one of—N(R¹)SO₂(CHR¹)_(n)R² or —(C₁-C₆)alkylN(R¹)SO₂(CHR¹)_(n)R², wherein eachR¹ is independently selected from hydrogen, (C₁-C₆)alkyl, phenyl andbenzyl; R² is aryl, heteroaryl or heterocycloalkyl optionallysubstituted with one or more substituents independently selected fromhalogen, OH, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, trifluoromethoxy,—S(O)_(m)(C₁-C₆)alkyl, amino, —N(R¹)CO(C₁-C₆)alkyl, COOR¹,—(C₁-C₆)alkylCOOR¹, —CO(C₁-C₆)alkyl, —(C₁-C₆)alkylOH,—(C₁-C₆)alkylamino, di-((C₁-C₆)alkyl)amino, nitro, cyano,—CONH(CHR¹)_(n)CO₂R¹, —CONR¹N(R¹)₂, trifluoromethyl, aryl, heteroaryl,and heterocycloalkyl; n is an integer from 0 to 6; and m is an integerfrom 0 to 2;

with the proviso that the cycloalkenyl ring is not aromatic.

Where R is a cyclohexyl or cyclohexenyl ring, the ring is preferablysubstituted at the 3- or 4-position, and more preferably at the4-position.

Where R is a cyclopentyl or cyclopentenyl ring, the ring is preferablysubstituted at the 3-position.

In a preferred embodiment, R is substituted by one of—(C₁-C₆)alkylN(R¹)SO₂(CHR¹)_(n)R².

In a further preferred embodiment, R is substituted by one of—N(R¹)SO₂(CHR¹)_(n)R².

In a preferred embodiment, R¹ is H.

In a preferred embodiment, n is 0.

In a preferred embodiment, n is 1.

In a preferred embodiment, n is 2.

In a preferred embodiment, m is 2.

In a preferred embodiment, R¹ is H; and n is 0.

-   N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-(trifluoromethyl)benzenesulfonamide;-   N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3,5-bis(trifluoromethyl)benzene    sulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl](phenyl)methanesulfonamide;-   2-Chloro-N-[cis-4-(2,4-dihydroxyphenyl    )cyclohexyl]-5-(trifluoromethyl)benzene sulfonamide;-   3,5-Dichloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide;-   4-Bromo-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]-2,5-difluorobenzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3,5-bis(trifluoromethyl)benzene    sulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-naphthalenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-(hydroxymethyl)benzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-(hydroxymethyl)benzene    sulfonamide;

4-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic acid;

-   3-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic    acid;-   4-({[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic    acid;-   3-({[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic    acid;-   Benzyl    (2S)-2-{[3-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoyl]amino}-3-phenylpropanoate;-   (2S)-2-([3-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]aminosulfonyl)benzoyl]amino)-3-phenylpropanoic    acid;-   Benzyl    3-[3-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoyl]amino)propanoate;-   N-[3-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoyl]-β-alanine;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-hydrazinocarbonyl)benzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-(1H-tetrazol-5-yl)benzenesulfonamide;    and a pharmaceutically acceptable salt thereof.

The present invention further provides a pharmaceutical composition forlightening skin or reducing the pigmentation of skin in a human,comprising a pharmaceutically acceptable carrier, and a skin-lighteningor pigmentation-reducing effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R is a (C₃-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring, whereineither the cycloalkyl ring or cycloalkenyl ring is substituted by one of—N(R¹)SO₂(CHR¹)_(n)R² or —C₁-C₆)alkylN(R¹)SO₂(CHR¹)_(n)R², wherein eachR¹ is independently selected from hydrogen, (C₁-C₆)alkyl, phenyl andbenzyl; R² is aryl, heteroaryl or heterocycloalkyl optionallysubstituted with one or more substituents independently selected fromhalogen, OH, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, trifluoromethoxy,—S(O)_(m)(C₁-C₆)alkyl, amino, —N(R¹)CO(C₁-C₆)alkyl, COOR¹,—(C₁-C₆)alkylCOOR¹, —CO(C₁-C₆)alkyl, —(C₁-C₆)alkylOH,—(C₁-C₆)alkylamino, di-((C₁-C₆)alkyl)amino, nitro, cyano,—CONH(CHR¹)_(n)CO₂R¹, —CONR¹N(R¹)₂, trifluoromethyl, aryl, heteroaryl,and heterocycloalkyl; n is an integer from 0 to 6; and m is an integerfrom 0 to 2;

with the proviso that the cycloalkenyl ring is not aromatic.

Where R is a cyclohexyl or cyclohexenyl ring, the ring is preferablysubstituted at the 3- or 4-position, and more preferably at the4-position.

Where R is a cyclopentyl or cyclopentenyl ring, the ring is preferablysubstituted at the 3-position.

In a preferred embodiment, R is substituted by one of—C₁-C₆)alkylN(R¹)SO₂(CHR¹)_(n)R².

In a further preferred embodiment, R is substituted by one of—(C₁-C₆)alkylN(R¹)SO₂(CHR¹)_(n)R².

In a preferred embodiment, R¹ is H.

In a preferred embodiment, n is 0.

In a preferred embodiment, n is 1.

In a preferred embodiment, n is 2.

In a preferred embodiment, m is 2.

In a preferred embodiment, R¹ is H; and n is 0.

In a preferred embodiment, R¹ is H; n is 0; and m is 2.

In a preferred embodiment, the pharmaceutical composition of the presentinvention is adapted for topical application.

The invention further provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a skin-lightening orpigmentation-reducing effective amount of a compound selected from thegroup consisting of:

-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]benzenesulfonamide;-   4-Chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide;-   3-Chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]-4-fluorobenzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2-thiophenesulfonamide;-   5-Chloro-N-[cis-4-(2,4-dihydroxyphenyl    )cyclohexyl]-2-thiophenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-nitrobenzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-nitrobenzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2,4-dinitrobenzenesulfonamide;-   3-Cyano-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]4-(methylsulfonyl)benzenesulfonamide;-   N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]benzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2-naphthalenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-methylbenzenesulfonamide;-   N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-methylbenzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-methoxybenzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-5-(dimethylamino)-1-naphthalenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-methyl-1H-imidazole-4-sulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-5-(3-isoxazolyl)-2-thiophenesulfonamide;-   Methyl    3-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoate;-   Methyl    4-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoate;-   Methyl    3-({[trans-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoate;-   Methyl    4-({[trans-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoate;-   4-Cyano-N-[trans-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide;-   N-[2-Chloro-4-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)phenyl]acetamide;-   4-Amino-3-chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide;-   4-Acetyl-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-(trifluoromethoxy)benzenesulfonamide;-   N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-fluorobenzenesulfonamide;-   N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2    ,4-difluorobenzenesulfonamide;-   N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2,3,4,5,6-pentafluorobenzene    sulfonamide;-   N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-(trifluoromethyl)benzenesulfonamide;-   N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3,5-bis(trifluoromethyl)benzene    sulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl](phenyl)methanesulfonamide;-   2-Chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]-5-(trifluoromethyl)benzene    sulfonamide;-   3,5-Dichloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide;-   4-Bromo-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]-2,5-difluorobenzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3,5-bis(trifluoromethyl)benzene    sulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-naphthalenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-(hydroxymethyl)benzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-(hydroxymethyl)benzene    sulfonamide;-   4-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic    acid;-   3-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic    acid;-   4-({[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic    acid;-   3-({[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic    acid;-   Benzyl    (2S)-2-[3-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoyl]amino}-3-phenylpropanoate;-   (2S)-2-{[3-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoyl]amino}-3-phenylpropanoic    acid;-   Benzyl    3-{[3-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoyl]amino}propanoate;-   N-[3-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoyl]-β-alanine;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-hydrazinocarbonyl)benzenesulfonamide;-   N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-(1H-tetrazol-5-yl)benzenesulfonamide;    and a pharmaceutically acceptable salt thereof.

The invention further provides a cosmetic composition comprising atopical carrier in combination with any one or more of the compounds offormula I, or a pharmaceutically acceptable salt thereof.

The present invention further provides a method of lightening skin in ahuman, comprising administering to said human a skin-lightening orpigmentation-reducing effective amount of a compound of formula I or apharmaceutically acceptable salt thereof. In a preferred embodiment, thepresent invention provides a method of lightening skin in a human inneed of said treatment, comprising administering to said human askin-lightening effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

The present invention further provides a method of inhibiting tyrosinasein a human, comprising administering to said human atyrosinase-inhibiting effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof. In a preferred embodiment, thepresent invention provides a method of inhibiting tyrosinase in a humanin need of said treatment, comprising administering to said human atyrosinase-inhibiting effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

The present invention further provides a topical or transdermalpharmaceutical composition for the treatment of an inflammatory disorderor condition such as psoriasis, dermatitis or acne, or for the treatmentof dandruff, in a human in need of said treatment, comprising apharmaceutically acceptable carrier, and an amount of a compound offormula I, or a pharmaceutically acceptable salt thereof, which amountis effective in treating such disorder or condition.

The present invention further provides a method of treating aninflammatory disorder, such as psoriasis, dermatitis or acne, or amethod of treating dandruff, in a human in need of said treatment,comprising administering to said human an amount of a compound offormula I or a pharmaceutically acceptable salt thereof, which amount iseffective in treating such disorder or condition.

The present invention further provides a kit, comprising a containercomprising one or more specific compounds or pharmaceutically acceptablesalts thereof, or pharmaceutical compositions, of the present inventionthat lighten skin. The kit may further comprise printed instructions asa label or package insert directing the use of the enclosed compound orcomposition to lighten skin pigmentation.

As used herein, the terms “treat” and “treating”, and the like, refer toreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, refers to the act of treating, as “treating” is definedimmediately above.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof. Any substituents or functionalgroups on the alkyl group, as indicated herein, can be substitutedanywhere on the alkyl group.

The term “aryl”, as used herein, refers to phenyl or naphthyl. The arylgroup can be optionally substituted with one or more substituents,preferably from one to two substituents, independently selected fromhalogen, OH, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, trifluoromethoxy,—S(O)_(m)(C₁-C₆)alkyl, amino, —N(R¹)CO(C₁-C₆)alkyl, COOR¹,—(C₁-C₆)alkylCOOR¹, —CO(C₁-C₆)alkyl, —(C₁-C₆)alkylOH,—(C₁-C₆)alkylamino, di-((C₁-C₆)alkyl)amino, nitro, cyano,—CONH(CHR¹)_(n)CO₂R¹, —CONR¹N(R¹)₂, and trifluoromethyl. Anysubstituents or functional groups on the aryl group, as indicatedherein, can be substituted anywhere on the aryl group.

The term “one or more substituents”, as used herein, refers to a numberof substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites.

The term “halo”, as used herein, refers to halogen and, unless otherwiseindicated, includes chloro, fluoro, bromo and iodo.

The term “heteroaryl”, as used herein, refers to (C₂-C₉)heteroaryl, andpreferably a 5- or 6-membered heteroaryl, containing one to five N, O orS atoms. In a preferred embodiment, the heteroaryl is selected fromfuryl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl,purinyl, 6,7-dihydro-5H-[1]pyridinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolinyl, quinolinyl, phthalazinyl,quinoxalinyl, quinazolinyl, and benzoxazinyl. One of ordinary skill inthe art will understand that the connection of said (C₂-C₉)heteroarylring can be through a carbon atom or through a nitrogen heteroatom wherepossible.

In a preferred embodiment, the heteroaryl group is optionallysubstituted with one or more substituents, preferably from one to twosubstituents, independently selected from halogen, OH, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, trifluoromethoxy, —S(O)_(m)(C₁-C₆)alkyl, amino,—N(R¹)CO(C₁-C₆)alkyl, COOR¹, —(C₁-C₆)alkylCOOR¹, —CO(C₁-C₆)alkyl,—(C₁-C₆)alkylOH, —(C₁-C₆)alkylamino, di-((C₁-C₆)alkyl)amino, nitro,cyano, —CONH(CHR¹)_(n)CO₂R¹, —CONR¹N(R¹)₂, and trifluoromethyl. Anysubstituents or functional groups on the heteroaryl group, as indicatedherein, can be substituted anywhere on the heteroaryl group.

The term “heterocycloalkyl”, as used herein, refers to a(C₂-C₉)heterocycloalkyl, and preferably a 5- or 6-memberedheterocycloalkyl, containing one to five N, O or S atoms. In a preferredembodiment, the heterocycloalkyl group is selected from pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, and chromanyl. One of ordinary skill inthe art will understand that the connection of said heterocycloalkylring can be through a carbon atom or through a nitrogen heteroatom wherepossible.

In a preferred embodiment, the heterocycloalkyl group is optionallysubstituted with one or more substituents, preferably from one to twosubstituents, independently selected from halogen, OH, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, trifluoromethoxy, —S(O)_(m)(C₁-C₆)alkyl, amino,—N(R¹)CO(C₁-C₆)alkyl, COOR¹, —(C₁-C₆)alkylCOOR¹, —CO(C₁-C₆)alkyl,—(C₁-C₆)alkylOH, —(C₁-C₆)alkylamino, di-((C₁-C₆)alkyl)amino, nitro,cyano, —CONH(CHR¹)_(n)CO₂R¹, —CONR¹N(R¹)₂, and trifluoromethyl. Anysubstituents or functional groups on the heterocycloalkyl group, asindicated herein, can be substituted anywhere on the aryl group.

Compounds of formula I may contain chiral centers and therefore mayexist in different enantiomeric and diastereomeric forms. This inventionrelates to all optical isomers, stereoisomers and tautomers of thecompounds of formula I, and mixtures thereof, and to all pharmaceuticalcompositions and methods of treatment defined above that contain oremploy them, respectively.

Formula I, as defined above, also includes compounds identical to thosedepicted but for the fact that one or more hydrogen, carbon or otheratoms are replaced by isotopes thereof. Such compounds may be useful asresearch and diagnostic tools in metabolism pharmacokinetic studies andin binding assays.

The present invention also relates to the pharmaceutically acceptableacid addition and base salts of any of the aforementioned compounds offormula I. The acids that are used to prepare the pharmaceuticallyacceptable acid addition salts of the aforementioned base compounds ofthis invention are those that form non-toxic acid addition salts, i.e.,salts containing pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acetate, lactate, citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

As used herein, a “skin-lightening or pigmentation reducing amount of acompound of formula I”, and the like, means an amount or concentrationof the compound capable of detectably lightening skin or reducingpigmentation in a human, as determined by any standard assay. The activecompound is typically administered in a pharmaceutical composition andfor a standard course of treatment that produces the desired result ofskin depigmentation.

As used herein, a “tyrosinase-inhibiting effective amount of a compoundof formula I”, and the like, means an amount or concentration of thecompound capable of detectably inhibiting tyrosinase activity in ahuman, as determined by any standard assay, such as those describedbelow.

As used herein, an “amount of a compound of formula I capable oftreating an inflammatory disorder such as psoriasis, dermatitis or acne,or treating dandruff”, and the like, means an amount or concentration ofthe compound capable of detectably ameliorating, reducing, eliminating,slowing, or preventing the progression of, any symptom or conditionassociated with or caused by such disorder or condition, in a human, asdetermined by any standard assay.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I may be prepared as described in the followingreaction schemes and discussion. Unless otherwise indicated, R¹ andstructural formula I in the reaction schemes and discussion that followare as defined above.

Referring to Scheme 1, where x is zero to five, compounds of formula (2)can be prepared starting with compound (1), which is commerciallyavailable (Aldrich Chemical Co.). A suitable protecting group can beselected as will be evident to those of skill in the art and conversionto compounds of formula (2) can occur under standard conditions. Oneexample of a suitable protecting group is benzyl, and condensation canoccur between compound (1) and benzyl alcohol with the removal of waterusing Dean-Stark apparatus to give compounds of formula (2). Compoundsof formula (3), where T is a sulfonamide moiety have been previouslyreported (Fonken, G. S. et al. J. Org. Chem., 1968, 33, 3182 andDubuffet, T. et al. Synth. Commun., 1997, 27, 1123). Alternatively, T isa functional group that may be converted to a sulfonamide using standardchemistry that will be obvious to those with skill in the art.Condensation of compounds of formula (2) with compounds of formula (3)may occur using standard techniques, for instance, treatment ofcompounds of formula (2) with a base, such as lithium diisopropylamideor lithium hexamethyldisilazide, in an ethereal solvent followed by theaddition of a compound of formula (3) would give compounds of formula(4). When W is hydrogen (H), as opposed to a protecting group (PG),condensation of compounds of formula (2) with compounds of formula (3)requires the use of at least two equivalents of a suitable base such aslithium diisopropylamide in a suitable solvent such as tetrahydrofuran,with a suitable co-solvent such as hexamethylphosphoramide. Treatment ofcompounds of formula (4) with a suitable halogenating reagent such as,for example, N-bromosuccinimide in a chlorinated solvent, such asdichloromethane or chloroform, at about room temperature, can givecompounds of formula (5) where Q is halo, and preferably bromo. Where Wis H, the compound of formula (5) may exist in equilibrium with thecompound of formula (5′).

Compounds of formula (6) may be generated from compounds of formula (5)or (5′) under suitable conditions. Such conditions may involve treatingcompounds of formula (5) or (5′) with a base such as, e.g.,1,8-diazobicyclo[5.4.0]undec-7-ene in a suitable solvent such asN,N-dimethylformamide at about room temperature. Where T represents asulfonamide moiety, compounds of formula (7) may be generated fromcompounds of formula (5), (5′) or (6) under suitable reactionconditions. Such conditions may involve treating compounds of formula(5) or (5′) or (6) with a base such as, e.g.,1,8-diazobicyclo[5.4.0]undec-7-ene in a suitable solvent such asN,N-dimethylformamide at about 140° C. Other solvents such as toluene orN-methylpyrrolidinone may also be useful for this purpose. Where Trepresents a sulfonamide moiety, compounds of formula (8) may begenerated from compounds of formula (6) using standard techniques, e.g.,treating compounds of formula (6) with triethylsilane in the presence ofa Lewis acid such as boron trifluoride in a chlorinated solvent.Hydrogenation of compounds of formula (7) under standard conditions,e.g., hydrogen gas and palladium on charcoal in ethanol, also yieldscompounds of formula (8). Where W is a protecting group, compounds offormula (I) can be formed by treating compounds of formula (7) or (8)under standard conditions that will be obvious to those with skill inthe art. Where T is not a sulfonamide group, compounds of formula (7)and (8) may be converted into compounds of formula (I) using standardchemistry that will be obvious to those with skill in the art.

Referring to Scheme 2, as an example of a more specific scheme where x′is zero or one, compounds of formula (9) can be prepared starting withcompound (1). Conversion to compounds of formula (9) can occur understandard conditions, for instance where the protecting group is benzyl,condensation can occur between compound (1) and benzyl alcohol with theremoval of water using Dean-Stark apparatus. Condensation of compoundsof formula (9) with compounds of formula (10) may occur using standardtechniques, for instance, treatment of compounds of formula (9) with abase such as lithium diisopropylamide in an ethereal solvent followed bythe addition of a compound of formula (10) (where x′=1, compound (10) iscommercially available from Aldrich Chemical Co.) would give compoundsof formula (11). Treatment of compounds of formula (11) with a suitablebrominating reagent, such as N-bromosuccinimide, in a chlorinatedsolvent at about room temperature, can give compounds of formula (12).Compounds of formula (13) may then be generated from compounds offormula (12) under suitable reaction conditions. Such conditions mayinvolve treating compounds of formula (12) with a base such as1,8-diazobicyclo[5.4.0]undec-7-ene in a suitable solvent such asN,N-dimethylformamide at about 140° C. Subjection of compounds offormula (13) to standard hydrogenation conditions, e.g., hydrogen gasand palladium on charcoal in an ethanol/tetrahydrofuran mixture, yieldscompounds of the general formula (14) when the protecting group wasbenzyl. Compounds of formula (15) may then be obtained by subjectingcompounds of formula (14) to acidic conditions.

Protection of compounds of formula (15) with a suitable protecting groupsuch as tert-butyldimethylsilyl can occur under standard conditions,e.g., compounds of formula (15) can be treated withtert-butyldimethylsilyl chloride and a suitable base such as imidazole,in a suitable solvent such as dimethylformamide at about roomtemperature. Treatment of compounds of formula (16) with an amine underreductive amination conditions, e.g., where R¹=benzyl, using benzylamineand sodium triacetoxyborohydride in a suitable solvent (dichloroethane)can give compounds of formula (17). Alternatively, compounds of formula(17) can be formed by treating compounds of formula (16) with an amine,such as benzylamine, under dehydrating conditions followed by reactionwith a reducing agent such as sodium borohydride. Where R¹=benzyl,conversion of compounds of formula (17) to compounds of formula (18) canoccur using hydrogenolysis under standard conditions, e.g., palladium oncharcoal, hydrogen gas, in a suitable solvent, e.g. ethanol. Synthesisof compounds of formula I, where Y is —(CHR¹)_(n)R², can be obtainedusing conventional methods. For example, compounds of formula (17) and(18) can react with sulfonyl chlorides in a chlorinated solvent in thepresence of a base (e.g. triethylamine) at about room temperature.Subsequent functional group manipulation or derivatisation of Y can becarried out using chemistry that will be obvious to those with skill inthe art, and if applicable, deprotection using suitable deprotectionconditions, will provide further compounds of formula (I). An example offurther functional group manipulation that may occur is when Y issubstituted with a carboxylic ester. Treatment with a reducing agentsuch as lithium aluminium hydride in an ethereal solvent such astetrahydrafuran would give a compound in which Y is substituted with amethyl alcohol moiety.

It will be appreciated by those of skill in the art that in theprocesses described above, the functional groups of intermediatecompounds may need to be protected by protecting groups. The use ofprotecting groups is well-known in the art, and is fully described,among other places, in: Protecting Groups in Organic Chemistry, J. W. F.McOmie, (ed.), 1973, Plenum Press; and in: Protecting Groups in OrganicSynthesis, 2^(nd) edition, T. W. Greene & P. G. M. Wutz, 1991,Wiley-Interscience, which are incorporated by reference in theirentirety.

The compounds of formula I that are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of formula I from the reaction mixture as apharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the activebase compounds of this invention are readily prepared by treating thebase compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent, such as methanol or ethanol. Upon careful evaporationof the solvent, the desired solid salt is readily obtained.

Those compounds of formula I that are acidic in nature are capable offorming base salts with various pharmaceutically acceptable cations.Examples of such salts include the alkali metal and alkaline earth metalsalts and, particularly, the sodium and potassium salts. These salts canbe prepared by conventional techniques. The chemical bases that are usedas reagents to prepare the pharmaceutically acceptable base salts ofthis invention are those that form non-toxic base salts with the acidiccompounds of formula I. Such non-toxic base salts include those derivedfrom such pharmaceutically acceptable cations as sodium, potassium,calcium and magnesium, etc. These salts can easily be prepared bytreating the corresponding acidic compounds with an aqueous solutioncontaining the desired pharmaceutically acceptable cations, and thenevaporating the resulting solution to dryness, preferably under reducedpressure. Alternatively, they can also be prepared by mixing loweralkanolic solutions of the acidic compounds and the desired alkali metalalkoxide together, and then evaporating the resulting solution todryness, as described above. In either case, stoichiometric quantitiesof reagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final products.

Compounds of formula I and their pharmaceutically acceptable salts(hereinafter “the active compounds used in this invention”) are usefulin the treatment of disorders of human pigmentation, including solar andsimple lentigines (including age/liver spots), melasma/chloasma andpostinflammatory hyperpigmentation. The active compounds used in thisinvention reduce skin melanin levels by inhibiting the production ofmelanin, whether the latter is produced constitutively or in response toUV irradiation (such as sun exposure). Thus, the active compounds usedin this invention can be used to reduce skin melanin content innon-pathological states so as to induce a lighter skin tone, as desiredby the user, or to prevent melanin accumulation in skin that has beenexposed to UV irradiation. Thus, the active compounds used in thisinvention can be used simply to lighten skin where no pathological ordisease condition exists. The active compounds used in this inventioncan also be used for cosmetic purposes. As used herein to refer to thedepigmentation aspect of the invention, the term “a human in need ofsaid treatment” refers to a human who, for any reason, whether medicalor cosmetic, desires to reduce the melanin content of their skin or toprevent the melanization of their skin on any portion of their body.

The compounds of this invention can be mixed as cosmetics, quasi-drugs(where applicable), or pharmaceutical drugs. The compounds of thisinvention can appropriately be mixed with other components. Examples ofsuch components include oily components such as hydrocarbons, fats andoils such as liquid paraffin, squalene, vaseline, cetyl alcohol,isostearyl alcohol, cetyl-2-ethylhexanoate, 2-octyldodecyl alcohol,glycerin triiostearate, nut oils, and lanolin, as well as wax, silicone,surfactants, thickeners, neutralizers, antiseptics, germicides,anti-oxidants, powder components, pigments, perfumes, ultraviolet lightabsorbents, drugs, metallic sealant, and pH modifiers.

Occurrences in the skin or hair of noticeable but undesired pigmentationas a result of melanin production, overproduction or underproduction canbe treated using the methods of the present invention. Cosmeticapplications for methods of the present invention include the topicalapplication of compositions containing one or more of the compounds ofthe present invention to enhance or otherwise alter the visualappearance of skin or hair. The cosmetic compositions of the presentinvention are also useful to provide a smoother or softer skinappearance or texture.

The active compounds used in this invention can also be used incombination with skin peeling agents (including glycolic acid ortrichloroacetic acid face peels) to lighten skin tone and preventrepigmentation. The appropriate dose regimen, the amount of each doseadministered, and specific intervals between doses of the activecompound will depend upon the particular active compound employed. thecondition of the patient being treated, and the nature and severity ofthe disorder or condition being treated. Preferably, the active compoundis administered in an amount and at an interval that results in thedesired treatment of or improvement in the disorder or condition beingtreated.

An active compound used in this invention can also be used incombination with sun screens (UVA or UVB blockers) to preventrepigmentation; to protect against sun or UV-induced skin darkening orto enhance their ability to reduce skin melanin and their skin bleachingaction. An active compound used in this invention can also be used incombination with retinoic acid or its derivatives or any compounds thatinteract with retinoic acid receptors and accelerate or enhance theinvention's ability to reduce skin melanin and skin bleaching action, orenhance the invention's ability to prevent the accumulation of skinmelanin. An active compound used in this invention can also be used incombination with 4-hydroxyanisole. An active compound used in thisinvention can also be used in combination with ascorbic acid, itsderivatives and ascorbic-acid based products (such as magnesiumascorbate) or other products with an anti-oxidant mechanism (such asresveratrol) which accelerate or enhance their ability to reduce skinmelanin and their skin bleaching action.

As one skilled in the art would know in view of this disclosure, anactive compound used in the methods of the present invention may be usedalone or in combination with other compounds known in the art to affectmelanin synthesis, particularly other melanin synthesis inhibitors,including tyrosinase inhibitors. Such inhibitors include those currentlyknown in the art and those to be developed in the future. Knowninhibitors include various resorcinol derivatives, kojic acidderivatives, hydroquinone, melamine, and various types of plantextracts, among others. For example, any of the compounds used accordingto a skin-lightening method of the present invention may be used incombination with a tyrosinase inhibitor or other skin-whitening agent,including any one or more of those agents, including compounds orextracts, described in the following patent publications: U.S. Pat. No.4,278,656 to Nagai et al, issued Jul. 14, 1981, describing the use ofkojic acid and its derivatives; U.S. Pat. No. 4,369,174 to Nagai et al.,issued Jan. 18, 1983, describing the use of kojic acid and itsderivatives; U.S. Pat. No. 4,959,393 to Torihara et al., issued Sep. 25,1990, describing the use of 4-n-butylresorcinol, 4-isoamyl resorcinoland other resorcinol derivatives; U.S. Pat. No. 5,580,549 to Fukuda etal., issued Dec. 3, 1996, describing the use of various hydroxybenzoicacid derivatives; U.S. Pat. No. 6,123,959 to Jones et al., issued Sep.26, 2000, describing the use of liposomes containing combinations ofcompetitive inhibitors, such as arbutin, and non-competitive inhibitors,such as aloesin, of melanin synthesis; U.S. Pat. No. 6,132,740 to Hu,issued Oct. 17, 2000, describing the use of various resorcinolderivatives; U.S. Pat. No. 6,159,482 to Tuloup et al., issued Dec. 12,2000, describing the use of various hydroxyphenyl oxamate derivatives;WO 99/32077 by L'Oreal, published Jul. 1, 1999, describing the use ofvarious phenolic amides; WO 99/64025 by Fytokem Prod. Inc., publishedDec. 16, 1999, describing the use of various dicotyledonous plantextracts; WO 00/56702 by Pfizer Inc., published Sep. 28, 2000 describingvarious resorcinol derivatives; WO 00/76473 by Shiseido Co. Ltd.,published Dec. 12, 2000, describing the use of Withania plant extracts;EP 997146 by L'Oreal SA, published May 3, 2000, describing the use ofcombinations of mulberry and skullcap extracts with salicylic acidderivatives; JP 5221846 by Kunimasa Tomoji, published Aug. 31, 1993,describing the use of kojic acid derivatives; JP 7242687 by Shiseido Co.Ltd., published Sep. 19, 1995, describing the use of Trichodermaextracts; JP 7324023 by Itogawa H, published Dec. 12, 1995, describingthe use of Pseudostellariae radix extracts; JP 8012552 by Shiseido Co.Ltd., published Jan. 16, 1996, describing the use of Amor seco extracts;JP 8012554 by Shiseido Co. Ltd., published Jan. 16, 1996, describing theuse of Jabonciilo extracts; JP 8012557 by Shiseido Co. Ltd., publishedJan. 16, 1996, describing the use of Huaca extracts; JP 8012560 byShiseido Co. Ltd., published Jan. 16, 1996, describing the use ofCopaiba extracts; JP 8012561 by Shiseido Co. Ltd., published Jan. 16,1996, describing the use of Arnica extracts; JP 8134090 by Fujisawa,published May 28, 1996, describing the use of galactosyl-kojic acidderivatives; JP 8168378 by Kirinjo KK, published Jul. 2, 1996,describing the use of lees from rice wine production; JP 8277225 byKansai Koso KK, published Oct. 22, 1996, describing the use ofAutocarpus incisus extracts; JP 9002967 by Sanki Shoji KK, publishedJan. 7, 1997, describing the use of Prunus domesticus extracts; JP9295927 by Yagi Akira, published Nov. 18, 1997, describing the use ofAloe vera extracts; JP 10072330 by Kansai Kouso, published Mar. 17,1998, describing the use of oxydesberatrol derivatives; JP 10081626 byKamiyama KK, published Mar. 31, 1998, describing the use of4-substituted benzoic acids; JP 10101543 by Kansai Kouso KK, publishedApr. 21, 1998, describing the use of flavonoids; JP 11071231 by MaruzenPharm., published Mar. 16, 1999, describing the use of bakuchiol; JP11079934 by Kyodo Nyugyo, published Mar. 23, 1999, describing the use oflow molecular weight thiol from sake lees; JP 11246347 by Shiseido Co.Ltd., published Sep. 14, 1999, describing the use of Achilleamillefolium extracts; JP 11246344 by Shiseido Co. Ltd., published Sep.14, 1999, describing the use of Gliricidia extracts; JP 2000-080023 byKanebo Ltd., published Mar. 21, 2000, describing the use ofmetallothionine inducers; JP 2000-095663 by Kose KK, published Apr. 4,2000, describing the use of various plant extracts; JP 2000-159681 byHai Tai Confectionery Co. Ltd., published Jun. 13, 2000, describing theuse of grape seed extract; JP-7206753 by Nikken Food KK, published Aug.8, 1995, describing the use of dihydroxycurcumin derivatives; JP-5320025by Kunimasa T, published Dec. 3, 1993, describing the use of kojic acidderivatives; and JP-59157009 by Yakurigaku Chuou KE, published Sep. 6,1984, describing the use of β-thujaplicin, hydroquinone or a pyronecompound in combination with a melanin adsorbent; among others; whichpatent publications are incorporated herein by reference in theirentireties.

This invention relates both to methods of lightening or reducing thepigmentation of skin in which an active compound used in this invention,and one or more of the other active ingredients, such as those referredto above, are administered together as part of the same pharmaceuticalcomposition, as well as methods in which they are administeredseparately as part of an appropriate dose regimen designed to obtain thebenefits of the combination therapy. The appropriate dose regimen, theamount of each dose administered, and specific intervals between dosesof each active agent will depend upon the specific combination of activeagents employed, the condition of the patient being treated, and thenature and severity of the disorder or condition being treated. Suchadditional active ingredients will generally be administered in amountsless than or equal to those for which they are effective as singletopical therapeutic agents. The FDA approved dosages for such activeagents that have received FDA approval for administration to humans arepublicly available.

An active compound of this invention will generally be administered inthe form of a pharmaceutical composition comprising at least onecompound of formula (I), together with a pharmaceutically acceptablevehicle or diluent. Alternatively, an active compound of this inventioncan be administered in the form of a cosmetic composition comprising atleast one compound of formula (I), together with a cosmeticallyacceptable vehicle or diluent. Such a composition is generallyformulated in a conventional manner utilizing solid or liquid vehiclesor diluents as appropriate for topical administration, in the form ofsolutions, gels, creams, jellies, pastes, lotions, ointments, salves,aerosols and the like.

Examples of vehicles for application of the active compounds of thisinvention include an aqueous or water-alcohol solution, an emulsion ofthe oil-in-water or water-in-oil type, an emulsified gel, or a two-phasesystem. Preferably, the compositions according to the invention are inthe form of lotions, creams, milks, gels, masks, microspheres ornanospheres, or vesicular dispersions. In the case of vesiculardispersions, the lipids of which the vesicles are made can be of theionic or nonionic type, or a mixture thereof. Such vehicles can includesuitable viscosity enhancing agents, pH adjusting agents, stabilizers,fragrances, etc., as known in the art of topical formulations.

An effective dosage and treatment protocol can be determined byconventional means, starting with a low dose in laboratory animals andthen increasing the dosage while monitoring the effects, andsystematically varying the dosage regimen as well. Animal studies,preferably mammalian studies, are commonly used to determine the maximaltolerable dose, or MTD, of a bioactive agent per kilogram weight. Thoseskilled in the art can extrapolate doses for efficacy and avoidance oftoxicity to other species, including humans.

Before human studies of efficacy are undertaken, Phase I clinicalstudies in normal subjects can help establish safe doses. Numerousfactors can be taken into consideration by a clinician when determiningan optimal dosage for a given subject. Primary among these is thetoxicity and half-life of the chosen compound. Additional factorsinclude the size of the patient, the age of the patient, the generalcondition of the patient, the particular disease, condition, or disorderbeing treated, the severity of the disease, condition, or disorder beingtreated, the presence of other drugs in the patient, the effect desired,and the like. The trial dosages would be chosen after consideration ofthe results of animal studies and the clinical literature.

One of ordinary skill in the art will appreciate that the endpoint oftreatment chosen in a particular case will vary according to thedisease, condition, or disorder being treated, the outcome desired bythe patient, subject, or treating physician, and other factors. Wherethe composition is being used to lighten skin color such as, forexample, to reverse hyperpigmentation caused by, for example,inflammation or diseases such as melasma, or to lighten hair color, anyone of a number of endpoints can be chosen. For example, endpoints canbe defined subjectively such as, for example, when the subject is simply“satisfied” with the results of the treatment. For pharmacologicalcompositions, the endpoint can be determined by the patient's, or thetreating physician's, satisfaction with the results of the treatment.Alternatively, endpoints can be defined objectively. For example, thepatient's or subject's skin or hair in the treated area can be comparedto a color chart. Treatment is terminated when the color of the skin orhair in the treated area is similar in appearance to a color on thechart. Alternatively, the reflectance of the treated skin or hair can bemeasured, and treatment can be terminated when the treated skin or hairattains a specified reflectance. Alternatively, the melanin content ofthe treated hair or skin can be measured. Treatment can be terminatedwhen the melanin content of the treated hair or skin reaches a specifiedvalue. Melanin content can be determined in any way known to the art,including by histological methods, with or without enhancement by stainsfor melanin.

In the depigmenting compositions according to the present invention, theconcentration of the active compound of the invention is generallybetween 0.01 and 10%, preferably between 0.1 and 10%, relative to thetotal weight of the composition.

The compositions of this invention can optionally also contain amoistener, a surfactant, keratolytic, an anti-inflammatory agent, acomplexing agent, an antioxidant, a preservative, a colorant, afragrance, or a sunscreen.

The compositions of the present invention can be applied directly to theskin. Alternatively, they can be delivered by various transdermal drugdelivery systems, such as transdermal patches as known in the art. Forexample, for topical administration, the active ingredient can beformulated in a solution, gel, lotion, ointment, cream, suspension,paste, liniment, powder, tincture, aerosol, patch, or the like in apharmaceutically or cosmetically acceptable form by methods well knownin the art. The composition can be any of a variety of forms common inthe pharmaceutical or cosmetic arts for topical application to animalsor humans, including solutions, lotions, sprays, creams, ointments,salves, gels, etc., as described below. Preferred agents are those thatare viscous enough to remain on the treated area, those that do notreadily evaporate, and/or those that are easily removed by rinsing withwater, optionally with the aid of soaps, cleansers and/or shampoos.Actual methods for preparing topical formulations are known or apparentto those skilled in the art, and are described in detail in Remington'sPharmaceutical Sciences, 1990 (supra); and Pharmaceutical Dosage Formsand Drug Delivery Systems, 6th ed., Williams & Wilkins (1995).

In order to enhance the percutaneous absorption of the activeingredients, one or more of a number of agents can be added in thetopical formulations including, but not limited to, dimethylsulfoxide,dimethylacetamide, dimethylformamide, surfactants, azone, alcohol,acetone, propylene glycol and polyethylene glycol. In addition, physicalmethods can also be used to enhance transdermal penetration such as,e.g., by iontophoresis or sonophoresis. Alternatively, or in addition,liposomes may be employed.

A topically applied composition of the invention contains apharmaceutically effective agent that lightens skin as described herein,and those ingredients as are necessary for use as a carrier, such as anemulsion, a cream, an ointment, an aqueous solution, a lotion or anaerosol. Non-limiting examples of such carriers are described in moredetail below and may be found in International Patent Publication WO00/62742, published Oct. 26, 2000; U.S. Pat. No. 5,691,380 to Mason etal., issued Nov. 25, 1997; U.S. Pat. No. 5,968,528 to Deckner et al.,issued Oct. 19, 1999; U.S. Pat. No. 4,139,619 to Chidsey, III, issuedFeb. 13, 1979; and U.S. Pat. No. 4,684,635 to Orentreich et al., issuedAug. 4, 1987; which are incorporated herein by reference. Suitablepharmaceutical carriers are further described in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.(1990), which is a standard reference text in this field.

The pharmaceutical compositions of the invention may optionally includecomponents suitable for application to keratinous tissue, that is, whenincorporated into the composition, they are suitable for use in contactwith human keratinous tissue without undue toxicity, incompatibility,instability, allergic response, and the like within the scope of soundmedical judgment. In addition, such optional components are usefulprovided that they do not unacceptably alter the benefits of the activecompounds of the invention. The CTFA Cosmetic Ingredient Handbook,Second Edition (1992) describes a wide variety of non-limiting cosmeticand pharmaceutical ingredients commonly used in the skin care industry,which are suitable for use in the compositions of the present invention.Examples of these ingredient classes include: abrasives, absorbents,aesthetic components such as fragrances, pigments, colorings/colorants,essential oils, skin sensates, astringents, etc. (e.g., clove oil,menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, witch hazeldistillate), anti-acne agents, anti-caking agents, antifoaming agents,antimicrobial agents (e.g., iodopropyl butylcarbamate), antioxidants,binders, biological additives, buffering agents, bulking agents,chelating agents, chemical additives, colorants, cosmetic astringents,cosmetic biocides, denaturants, drug astringents, external analgesics,film formers or materials, e.g., polymers, for aiding the film-formingproperties and substantivity of the composition (e.g., copolymer ofeicosene and vinyl pyrrolidone), opacifying agents, pH adjusters,propellants, reducing agents, sequestrants, skin-conditioning agents(e.g., humectants, including miscellaneous and occlusive), skin soothingand/or healing agents (e.g., panthenol and derivatives (e.g., ethylpanthenol), aloe vera, pantothenic acid and its derivatives, allantoinand bisabolol and dipotassium glycyrrhizinate), skin treating agents,thickeners, and vitamins and derivatives thereof.

In addition to the pharmaceutically effective amount of an agentdisclosed herein, the topical compositions of the present invention alsocomprise a dermatologically acceptable carrier. The phrase“dermatologically acceptable carrier”, as used herein, means that thecarrier is suitable for topical application to the skin, i.e.,keratinous tissue, has good aesthetic properties, is compatible with theactive agents of the present invention and any other components, andwill not cause any safety or toxicity concerns. A safe and effectiveamount of carrier is from about 50% to about 99.99%, preferably fromabout 80% to about 99.9%, more preferably from about 90% to about 98%,and most preferably from about 90% to about 95% of the composition.

The carrier utilized in the compositions of the invention can be in awide variety of forms. These include emulsion carriers, including, butnot limited to, oil-in-water, water-in-oil, water-in-oil-in-water, andoil-in-water-in-silicone emulsions, a cream, an ointment, an aqueoussolution, a lotion or an aerosol. As will be understood by the skilledartisan, a given component will distribute primarily into either thewater or oil/silicone phase, depending on the watersolubility/dispersibility of the component in the composition.

Emulsions according to the present invention generally contain apharmaceutically effective amount of an agent disclosed herein and alipid or oil. Lipids and oils may be derived from animals, plants, orpetroleum and may be natural or synthetic (i.e., man-made). Preferredemulsions also contain a humectant, such as glycerin. Emulsions willpreferably further contain from about 1% to about 10%, more preferablyfrom about 2% to about 5%, of an emulsifier, based on the weight of thecarrier. Emulsifiers may be nonionic, anionic or cationic. Suitableemulsifiers are described in, for example, U.S. Pat. No. 3,755,560 toDickert et al., issued Aug. 28, 1973; U.S. Pat. No. 4,421,769 to Dixon,et al., issued Dec. 20, 1983; and McCutcheon's Detergents andEmulsifiers, North American Edition, pages 317-324 (1986).

The emulsion may also contain an anti-foaming agent to minimize foamingupon application to the keratinous tissue. Anti-foaming agents includehigh molecular weight silicones and other materials well known in theart for such use.

Suitable emulsions may have a wide range of viscosities, depending onthe desired product form. Exemplary low viscosity emulsions, which arepreferred, have a viscosity of about 50 centistokes or less, morepreferably about 10 centistokes or less, most preferably about 5centistokes or less. The emulsion may also contain an anti-foaming agentto minimize foaming upon application to the keratinous tissue.Anti-foaming agents include high molecular weight silicones and othermaterials well known in the art for such use.

One type of emulsion is a water-in-silicone emulsion. Water-in-siliconeemulsions contain a continuous silicone phase and a dispersed aqueousphase. Preferred water-in-silicone emulsions of the present inventioncomprise from about 1% to about 60%, preferably from about 5% to about40%, more preferably from about 10% to about 20%, by weight of acontinuous silicone phase. The continuous silicone phase exists as anexternal phase that contains or surrounds the discontinuous aqueousphase described hereinafter.

The continuous silicone phase may contain a polyorganosiloxane oil. Apreferred water-in-silicone emulsion system is formulated to provide anoxidatively stable vehicle for delivery of a pharmaceutically effectiveamount of an agent disclosed herein. The continuous silicone phase ofthese preferred emulsions comprises between about 50% and about 99.9% byweight of organopolysiloxane oil and less than about 50% by weight of anon-silicone oil. In an especially preferred embodiment, the continuoussilicone phase comprises at least about 50%, preferably from about 60%to about 99.9%, more preferably from about 70% to about 99.9%, and evenmore preferably from about 80% to about 99.9%, polyorganosiloxane oil byweight of the continuous silicone phase, and up to about 50%non-silicone oils, preferably less than about 40%, more preferably lessthan about 30%, even more preferably less than about 10%, and mostpreferably less than about 2%, by weight of the continuous siliconephase. These useful emulsion systems may provide more oxidativestability over extended periods of time than comparable water-in-oilemulsions containing lower concentrations of the polyorganosiloxane oil.Concentrations of non-silicone oils in the continuous silicone phase areminimized or avoided altogether so as to possibly further enhanceoxidative stability of the active compound of the invention in thecompositions. Water-in-silicone emulsions of this type are described inU.S. Pat. No. 5,691,380 to Mason et al., issued Nov. 25, 1997.

The organopolysiloxane oil for use in the composition may be volatile,non-volatile, or a mixture of volatile and non-volatile silicones. Theterm “nonvolatile” as used in this context refers to those siliconesthat are liquid under ambient conditions and have a flash point (underone atmospheric of pressure) of or greater than about 100 degreesCelsius. The term “volatile” as used in this context refers to all othersilicone oils. Suitable organopolysiloxanes can be selected from a widevariety of silicones spanning a broad range of volatilities andviscosities. Examples of suitable organopolysiloxane oils includepolyalkylsiloxanes, cyclic polyalkylsiloxanes, andpolyalkylarylsiloxanes, which are known to those skilled in the art andcommercially available.

The continuous silicone phase may contain one or more non-silicone oils.Concentrations of non-silicone oils in the continuous silicone phase arepreferably minimized or avoided altogether so as to further enhanceoxidative stability of the pharmaceutically effective agent in thecompositions. Suitable non-silicone oils have a melting point of about25° C. or less under about one atmosphere of pressure. Examples ofnon-silicone oils suitable for use in the continuous silicone phase arethose well known in the chemical arts in topical personal care productsin the form of water-in-oil emulsions, e.g. mineral oil, vegetable oils,synthetic oils, semisynthetic oils, etc.

Useful topical compositions of the present invention comprise from about30% to about 90%, more preferably from about 50% to about 85%, and mostpreferably from about 70% to about 80% of a dispersed aqueous phase. Inemulsion technology, the term “dispersed phase” is a term well-known toone skilled in the art which means that the phase exists as smallparticles or droplets that are suspended in and surrounded by acontinuous phase. The dispersed phase is also known as the internal ordiscontinuous phase. The dispersed aqueous phase is a dispersion ofsmall aqueous particles or droplets suspended in and surrounded. by thecontinuous silicone phase described hereinbefore. The aqueous phase canbe water, or a combination of water and one or more water soluble ordispersible ingredients. Non-limiting examples of such optionalingredients include thickeners, acids, bases, salts, chelants, gums,water-soluble or dispersible alcohols and polyols, buffers,preservatives, sunscreening agents, colorings, and the like.

The topical compositions of the present invention typically comprisefrom about 25% to about 90%, preferably from about 40% to about 80%,more preferably from about 60% to about 80%, water in the dispersedaqueous phase by weight of the composition.

The water-in-silicone emulsions of the present invention preferablycomprise an emulsifier. In a preferred embodiment, the compositioncontains from about 0.1% to about 10% emulsifier, more preferably fromabout 0.5% to about 7.5%, most preferably from about 1% to about 5%,emulsifier by weight of the composition. The emulsifier helps disperseand suspend the aqueous phase within the continuous silicone phase.

A wide variety of emulsifying agents can be employed herein to form thepreferred water-in-silicone emulsion. Known or conventional emulsifyingagents can be used in the composition, provided that the selectedemulsifying agent is chemically and physically compatible with essentialcomponents of the composition, and provides the desired dispersioncharacteristics. Suitable emulsifiers include silicone emulsifiers,e.g., organically modified organopolysiloxanes, also known to thoseskilled in the art as silicone surfactants, non-silicon-containingemulsifiers, and mixtures thereof, known by those skilled in the art foruse in topical personal care products.

Useful emulsifiers include a wide variety of silicone emulsifiers. Thesesilicone emulsifiers are typically organically modifiedorganopolysiloxanes, also known to those skilled in the art as siliconesurfactants. Suitable emulsifiers are described, for example, inMcCutcheon's, Detergents and Emulsifiers, North American Edition (1986),published by Allured Publishing Corporation; U.S. Pat. No. 5,011,681 toCiotti et al., issued Apr. 30, 1991; U.S. Pat. No. 4,421,769 to Dixon etal., issued Dec. 20, 1983; and U.S. Pat. No. 3,755,560 to Dickert etal., issued Aug. 28, 1973.

Other preferred topical carriers include oil-in-water emulsions, havinga continuous aqueous phase and a hydrophobic, water-insoluble phase(“oil phase”) dispersed therein. Examples of suitable carrierscomprising oil-in-water emulsions are described in U.S. Pat. No.5,073,371 to Turner et al., issued Dec. 17, 1991; and U.S. Pat. No.5,073,372, to Turner et al., issued Dec. 17, 1991. An especiallypreferred oil-in-water emulsion, containing a structuring agent,hydrophilic surfactant and water, is described in detail hereinafter.

A preferred oil-in-water emulsion comprises a structuring agent toassist in the formation of a liquid crystalline gel network structure.Without being limited by theory, it is believed that the structuringagent assists in providing rheological characteristics to thecomposition which contribute to the stability of the composition. Thestructuring agent may also function as an emulsifier or surfactant.Preferred compositions of this invention comprise from about 0.5% toabout 20%, more preferably from about 1% to about 10%, most preferablyfrom about 1% to about 5%, by weight of the composition, of astructuring agent. The preferred structuring agents of the presentinvention are selected from the group consisting of stearic acid,palmitic acid, stearyl alcohol, cetyl alcohol, behenyl alcohol, stearicacid, palmitic acid, the polyethylene glycol ether of stearyl alcoholhaving an average of about 1 to about 21 ethylene oxide units, thepolyethylene glycol ether of cetyl alcohol having an average of about 1to about 5 ethylene oxide units, and mixtures thereof.

The preferred oil-in-water emulsions comprise from about 0.05% to about10%, preferably from about 1% to about 6%, and more preferably fromabout 1% to about 3% of at least one hydrophilic surfactant which candisperse the hydrophobic materials in the water phase (percentages byweight of the topical carrier). The surfactant, at a minimum, must behydrophilic enough to disperse in water. Suitable surfactants includeany of a wide variety of known cationic, anionic, zwitterionic, andamphoteric surfactants. See McCutcheon's. Detergents and Emulsifiers(1986), supra; U.S. Pat. No. 5,011,681 to Ciotti et al., issued Apr. 30,1991; U.S. Pat. No. 4,421,769 to Dixon et al. issued Dec. 20, 1983; andU.S. Pat. No. 3,755,560 to Dickert et al., issued Aug. 28, 1973. Theexact surfactant chosen depends upon the pH of the composition and theother components present. Preferred are cationic surfactants, especiallydialkyl quaternary ammonium compounds, examples of which are describedin U.S. Pat. No. 5,151,209 to McCall et al. issued Sep. 29, 1992; U.S.Pat. No. 5,151,210 to Steuri et al. issued Sep. 29, 1992; U.S. Pat. No.5,120,532 to Wells et al, issued Jun. 9, 1992; U.S. Pat. No. 4,387,090to Bolich Jr., issued Jun. 7, 1983; U.S. Pat. No. 3,155,591 to Hilfer,issued Nov. 3, 1964; U.S. Pat. No. 3,929,678 to Laughlin et al, issuedDec. 30, 1975; U.S. Pat. No. 3,959,461 to Bailey et al., May 25, 1976;McCutcheon's, Detergents & Emulsifiers (North American edition 1979)M.C. Publishing Co.; and Schwartz, et al., Surface Active Agents, TheirChemistry and Technology, New York: Interscience Publishers, 1949.

Alternatively, other useful cationic emulsifiers include amino-amides.Non-limiting examples of these cationic emulsifiers includestearamidopropyl PG-dimonium chloride phosphate, behenamidopropyl PGdimonium chloride, stearamidopropyl ethyldimonium ethosulfate,stearamidopropyl dimethyl (myristyl acetate) ammonium chloride,stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyldimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate,and mixtures thereof.

A wide variety of anionic surfactants are also useful herein. See, e.g.,U.S. Pat. No. 3,929,678, to Laughlin et al., issued Dec. 30, 1975. Inaddition, amphoteric and zwitterionic surfactants are also usefulherein.

The preferred oil-in-water emulsion comprises from about 25% to about98%, preferably from about 65% to about 95%, more preferably from about70% to about 90% water by weight of the topical carrier.

The hydrophobic phase is dispersed in the continuous aqueous phase. Thehydrophobic phase may contain water-insoluble or partially solublematerials such as are known in the art, including but not limited to thesilicones described herein in reference to silicone-in-water emulsions,and other oils and lipids such as described above in reference toemulsions.

The topical compositions of the subject invention, including but notlimited to lotions and creams, may comprise a dermatologicallyacceptable emollient. Such compositions preferably contain from about 2%to about 50% of the emollient. As used herein, “emollient” refers to amaterial useful for the prevention or relief of dryness, as well as forthe protection of the skin. A wide variety of suitable emollients areknown and may be used herein. See, e.g., Sagarin, Cosmetics, Science andTechnology, 2nd Edition, Vol. 1, pp. 3243 (1972), which containsnumerous examples of materials suitable as an emollient. A preferredemollient is glycerin. Glycerin is preferably used in an amount of fromor about 0.001 to or about 20%, more preferably from or about 0.01 to orabout 10%, most preferably from or about 0.1 to or about 5%, e.g., 3%.

Lotions and creams according to the present invention generally comprisea solution carrier system and one or more emollients. Lotions typicallycomprise from about 1% to about 20%, preferably from about 5% to about10% of emollient; from about 50% to about 90%, preferably from about 60%to about 80% water; and a pharmaceutically effective amount of an agentdescribed herein. A cream typically comprises from about 5% to about50%, preferably from about 10% to about 20% of emollient; from about 45%to about 85%, preferably from about 50% to about 75% water; and apharmaceutically effective amount of an agent described herein.

Ointments of the present invention may comprise a simple carrier base ofanimal or vegetable oils or semi-solid hydrocarbons (oleaginous);absorption ointment bases, which absorb water to form emulsions; orwater soluble carriers, e.g., a water soluble solution carrier.Ointments may further comprise a thickening agent, such as described inSagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp.72-73 (1972), incorporated herein by reference, and/or an emollient. Forexample, an ointment may comprise from about 2% to about 10% of anemollient; from about 0.1% to about 2% of a thickening agent; and apharmaceutically effective amount of an agent described herein.

By way of non-limiting example, 1000 g of topical cream is prepared fromthe following types and amounts of ingredients: a pharmaceuticallyeffective amount of an agent disclosed herein, tegacid regular (150 g)(a self-emulsifying glyceryl monostearate from Goldschmidt ChemicalCorporation, New York, N.Y.), polysorbate 80 (50 g), spermaceti (100 g),propylene glycol (50 g), methylparaben (19g), and deionized water insufficient quantity to reach 1000 gm. The tegacid and spermaceti aremelted together at a temperature of 70-80° C. The methylparaben isdissolved in about 500 g. of water and the propylene glycol, polysorbate80, and active compound are added in turn, maintaining a temperature of75-80° C. The methylparaben mixture is added slowly to the tegacid andspermaceti melt, with constant stirring. The addition is continued forat least 30 minutes with additional stirring until the temperature hasdropped to 40-45° C. Finally, sufficient water is added to bring thefinal weight to 1000 g. and the preparation stirred to maintainhomogeneity until cooled and congealed.

By way of non-limiting example, 1000 g of a topical ointment is preparedfrom the following types and amounts of ingredients: a pharmaceuticallyeffective amount of an agent disclosed herein, zinc oxide (50 g),calamine (50 g), liquid petrolatum (heavy) (250 g), wool fat (200 g),and enough white petrolatum to reach 1000 g. Briefly, the whitepetrolatum and wool fat are melted and 100 g of liquid petrolatum addedthereto. The pharmaceutically effective amount of an agent disclosedherein, zinc oxide, and calamine are added to the remaining liquidpetrolatum and the mixture milled until the powders are finely dividedand uniformly dispersed. The mixture is stirred into the whitepetrolatum, melted and cooled with stirring until the ointment congeals.

By way of non-limiting example, 1000 g of an ointment containing apharmaceutically effective amount of an agent disclosed herein isprepared from the following types and amounts of ingredients: apharmaceutically effective amount of an agent disclosed herein, lightliquid petrolatum (250 g), wool fat (200 g), and enough white petrolatumto reach 1000 g. Briefly, the pharmaceutically effective amount of anagent disclosed herein is finely divided and added to the light liquidpetrolatum. The wool fat and white petrolatum are melted together,strained, and the temperature adjusted to 45-50° C. The liquidpetrolatum slurry is added, and the ointment stirred until congealed.

By way of non-limiting example, 1000 ml of an aqueous solutioncontaining a pharmaceutically effective amount of an agent disclosedherein is prepared from the following types and amounts of ingredients:a pharmaceutically effective amount of an agent disclosed herein,polyethylene glycol 4000 (120 g) myristyl-gamma-picolinium chloride (0.2g), polyvinylpyrrolidone (1 g), and enough deionized water to reach 1000milliliters. Briefly, the ingredients are dissolved in the water and theresulting solution is sterilized by filtration.

By way of non-limiting example, 1000 g of lotion containing apharmaceutically effective amount of an agent disclosed herein isprepared from the following types and amounts of ingredients: apharmaceutically effective amount of an agent disclosed herein, N-methylpyrolidone (40 g), and enough propylene glycol to reach 1000 g.

By way of non-limiting example, an aerosol containing a pharmaceuticallyeffective amount of an agent disclosed herein is prepared from thefollowing types and amounts of materials: a pharmaceutically effectiveamount of an agent disclosed herein, absolute alcohol (4.37 g),dichlorodifluoroethane (1.43 g) and dichlorotetrafluoroethane (5.70 g).Briefly, the pharmaceutically effective amount of an agent disclosedherein is dissolved in the absolute alcohol and the resulting solutionfiltered to remove particles and lint. This solution is chilled to aboutminus 30° C. Then, to this is added the chilled mixture ofdichlorodifluoromethane and dichlorotetrafluoroethane.

For oral administration, gelatin capsules or liquid-filled soft gelatincapsules can contain the active ingredient and powdered or liquidcarriers, such as lactose, lecithin starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of hours. Compressed tablets can besugar-coated or film-coated to mask any unpleasant taste and to protectthe tablet from the atmosphere, or enteric-coated for selective,targeted disintegration in the gastrointestinal tract. Liquid dosageforms for oral administration can contain coloring and/or flavoring toincrease patient acceptance.

In general, sterile water, oil, saline, aqueous dextrose (glucose),polysorbate and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols, are suitable carriers for parenteralsolutions. Solutions or emulsions for parenteral administrationpreferably contain about 5-15% polysorbate 80 or lecithin, suitablestabilizing agents and, if necessary, buffer substances. Anti-oxidizingagents such as, but not limited to, sodium bisulfite, sodium sulfite, orascorbic acid, either alone or combined, are suitable stabilizingagents. Also useful are citric acid and its salts, and sodium EDTA. Inaddition, parenteral solutions can contain preservatives including, butnot limited to, benzalkonium chloride, methyl- or propyl-paraben, andchlorobutanol.

Additional examples of particular formulations comprising an activecompound of the present invention are provided below.

An example of the preparation of a topical gel follows. TABLE 1 TopicalGel: Ingredient Percent by Weight Active compound 0.50 Propylene glycol20.00 Ethanol 20.00 Carboxyvinyl polymer [Carbomer 940 ™] 1.00Hydroxyethyl cellulose 0.40 Benzyl alcohol 1.00 Sodium hydroxide 1N topH 6 Distilled water Balance

The components other than sodium hydroxide are combined to yield ahomogeneous dispersion. Addition of sodium hydroxide causes the mixtureto gel yielding a ready-to-use semisolid.

An example of the preparation of a topical cream follows. TABLE 2Topical Cream: Ingredient Percent by Weight Active compound 0.50 Stearicacid 7.00 Stearyl alcohol 5.00 Cetyl alcohol 2.00 Glycerin 10.00 Sodiumlaurylsulfate 1.00 Propylparaben 0.05 Methylparaben 0.25 Disodiumedetate 0.05 Distilled water Balance

The first four ingredients are heated to approximately 70° C. to producea uniform melt. The remaining ingredients are combined, heated toapproximately 75° C., and added with mixing to the previously preparedmelt. The emulsion thus formed is subsequently homogenized and cooled toyield a smooth white cream.

An example of the preparation of a topical lotion follows. TABLE 3Topical Lotion: Ingredient Percent by Weight Active compound 0.50Glyceryl monostearate 1.00 Isopropyl palmitate 4.00 Polyethylene glycol400 distearate 2.00 Glycerin 10.00 Methylparaben 0.10 Sodiumcetylsulfate 5.00 Distilled water Balance

The first four ingredients are combined and heated to approximately 70°C., then added with agitation to a mixture of the remaining ingredients,also at about 70° C. The emulsion is appropriately homogenized andcooled to produce a smooth, white, pourable lotion.

An example of the preparation of a topical solution follows. TABLE 4Topical Solution: Ingredient Percent by Weight Active compound 0.50Propylene glycol 20.00 Ethanol 50.00 Benzyl alcohol 1.00 Disodiumedetate 0.01 Propyl gallate 0.10 Citric acid 0.20 Sodium hydroxide 1N topH 6 Distilled water Balance

All ingredients except sodium hydroxide are combined with agitation, andthe pH of the resultant solution is adjusted with 1N sodium hydroxide,to pH 6, to yield a free-flowing, quick-drying topical solution.

The topical formulations presented herein are examples of typical gel,cream, lotion, or solution dosage forms of active compounds for use inlightening skin. Other optional components can be added or excipientratios can be adjusted to enhance cosmetic acceptability of theformulations. Additionally, these alterations can be made to customizethe composition toward a particular active compound, for example, toensure solubilization or to enhance chemical or physical stability.Optional components would include viscosity adjusters such ascelluloses, emollient oils such as mineral oil or glycerides, humectantssuch as polyols, cosolvents such as isopropyl alcohol or acetone,emulsifying agents of the anionic, cationic and non-ionic types,preservatives, antioxidants, opacifiers, colorants and perfumes.

An example of the preparation of an oral tablet formulation follows.TABLE 5 Tablet Formulation: Ingredient Amount (mg) Active Compound 25Lactose 50 Cornstarch (for mix) 10 Cornstarch (paste) 10 Magnesiumstearate (1%) 5 Total 100

The active compound, lactose, and cornstarch (for mix) are blended touniformity. The cornstarch (for paste) is suspended in 200 mL of waterand heated with stirring to form a paste. The paste is used to granulatethe mixed powders. The wet granules are passed through a No. 8 handscreen and dried at 80° C. The dry granules are lubricated with the 1%magnesium stearate and pressed into a tablet.

An example of the preparation of an oral solution follows. TABLE 6 OralSolution: Ingredient Percent by Weight Active Compound 2.0 Ethyl alcohol10.0 Benzyl alcohol 1.0 Peppermint flavor 0.2 Vanillin 0.2 Polysorbate40 0.1 Sucrose 50.0 Purified water Balance

The ingredients are combined and mixed to form a uniform solution.

As will be understood by those in the art, the compositions andpharmaceutical compositions of the invention may be provided as part ofa kit. Kits of the present invention comprise a container comprising oneor more specific compounds and/or pharmaceutical compositions of thepresent invention that lighten skin. The container is designed toprevent contamination, minimize evaporation or drying of thecomposition, etc. Optionally, the kit further comprises printedinstructions as a label or package insert directing the use of theenclosed compound or composition to lighten skin pigmentation. Thecompound or composition may or may not be provided in a preset unit doseor usage amount.

The ability of compounds of formula I to inhibit tyrosinase may bedetermined using any of the following procedures.

1. Tyrosinase (DOPA Oxidase) Assay Using Cell Lysate:

Human melanoma cell line, SKMEL 188 (licensed from MemorialSloan-Kettering), is used in the cell lysate assay and the screen. Inthe assay, compounds and L-dihydroxyphenylalanine (L-DOPA) (100 μg/ml)are incubated with the cell lysates containing human tyrosinase for 8hrs before the plates are read at 405 nm. Most of the compounds offormula I that were tested in this assay exhibited an IC₅₀ of 10 μM orless. For example, the compound of Example 14 below, i.e.,N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-methylbenzene sulfonamide,had an IC₅₀ in this assay of about 4 μm.

2. Melanin Assay in Human Primary Melanocytes:

Compounds are incubated with human primary melanocytes in the presenceof α-melanocyte stimulating hormone (α-MSH) for 2-3 days. Cells are thenlysed with sodium hydroxide and sodium dodecyl sulfate (SDS) and melaninsignals are read at 405 nm. Alternatively, ¹⁴C-DOPA is added to thecells in combination with tyrosinase inhibitors and acid-insoluble¹⁴C-melanin is quantitated by a scintillation counter. IC₅₀'s reflectthe inhibitory potency of the compounds in the new melanin synthesisthat was stimulated by α-MSH.

3. Tyrosine Kinase Assay (TK):

TK assays can be performed using purified tyrosine kinase domains ofc-met, erb-B2, or IGF-r. A specific antibody against phosphorylatedtyrosine residue is used in the assay. Colorimetric signals aregenerated by horseradish peroxidase, which is conjugated to theantibody.

4. Human Skin Equivalent Model:

A mixture of human melanocytes and keratinocytes is grown in anair-liquid interphase. This tissue culture forms a three-dimensionalstructure that histologically and microscopically resembles the humanskin epidermis. Test compounds are added on top of the cells to mimictopical drug application. After incubation with the compounds (10 μM)for 3 days, the cells are washed extensively and lysed for DOPA oxidaseassay.

5. IL-1 Assay (Interleukin-1 Assay):

An IL-1α ELISA assay (R&D system) can be used to evaluate the effect ofcompounds on IL-1 secretion in a human skin equivalent model. IL-1α is apro-inflammatory cytokine and plays a role in UV-induced skininflammation.

6. In Vivo Study:

Black or dark brown guinea pigs with homogeneous skin color can be usedin this study. A solution of the test compound of formula I (5% inethanol:propylene glycol, 70:30) and the vehicle control are applied tothe animals twice daily, 5 days per week for 4-8 weeks. Using thisassay, depigmentation can be determined by subtracting the lightreflectance of untreated skin from the light reflectance of treatedskin.

The present invention is illustrated by the following examples. It willbe understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (400 MHz ¹H NMR) were measuredfor solutions in d₆-DMSO, CDCl₃, or d₄-MeOH, and peak positions areexpressed in parts per million (ppm) downfield from tetramethylsilane(TMS). The peak shapes are denoted as follows: s, singlet; d, doublet;t, triplet; q, quartet, m, multiplet, b, broad.

The acronym PE refers to petroleum ether (B.p.=60-80° C.), HATU standsfor O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate. Flash column chromatography (FCC) was carried outon SiO₂. RP-HPLC refers to preparative reverse-phase high-performanceliquid chromatography. Mass spectra were obtained using an electrosprayionisation.

The following examples are illustrative only, and are not intended tolimit the scope of the present invention.

EXAMPLES Preparation 1 3(Benzyloxy)-2-cyclohexen-1-one

To a flask equipped with magnetic stirrer and Dean Stark apparatus wasadded 1,3-cyclohexanedione (70.0 g, 624 mmol), toluene (500 ml),p-toluenesulfonic acid monohydrate (1.68 g, 8.83 mmol) and benzylalcohol (65.6 g, 606 mmol). The resulting solution was heated underreflux for 2 hr. The reaction mixture was cooled to room temperature andwashed with saturated aqueous sodium carbonate solution (4×50 ml). Theorganic layer was washed with brine (50 ml), dried over magnesiumsulfate, filtered and concentrated in vacuo, affording a brown oil whichcrystallised upon standing. The crude crystalline material wastriturated in isopropyl ether (100 ml) and stirred at 0° C. for 2 hr.The mixture was filtered and the crystalline material was washed withice cold isopropyl ether (3×100 ml) followed by cold petroleum ether(100 ml). The resulting solid was dried overnight under reduced pressureto furnish the title compound (85.3 g, 68%). m/z (ES⁺) 203 (M+H⁺).

Preparation 2(±)-3-(Benzyloxy)-6-(8hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-2-cyclohexen-1-one

To a flask equipped with magnetic stirrer was added tetrahydrofuran (600ml) and diisopropylamine (38.1 ml, 272 mmol). The stirred solution wascooled to −78° C. and n-butyl lithium (113.4 ml, 272 mmol, 2.4 M inhexanes) was added dropwise via syringe. The resulting yellow solutionwas stirred for 35 min at −78° C., then 3-(benzyloxy)-2-cyclohexen-1-one(50.0 g, 248 mmol) was added as a solution in tetrahydrofuran (100 ml).The solution was stirred for 1 hr prior to the addition ofcyclohexane-1,4-dione monoethylene ketal (38.7 g, 248 mmol) as asolution in anhydrous tetrahydrofuran (100 ml). The solution was stirredfor 2 hr at −78° C., then allowed to warm slowly to room temperatureover 1 hr. Saturated aqueous ammonium chloride (80 ml) was added,followed by dichloromethane (700 ml) and the mixture stirred until nosolids remained. The layers were separated and the aqueous phaseextracted with dichloromethane (2×100 ml). The combined organic layerswere washed with brine (50 ml), dried over magnesium sulfate, thenconcentrated in vacuo. Trituration of the resulting solid with methanolafforded the title compound (78.4 g, 88%). m/z (ES⁺) 359 (M+H⁺).

Preparation 3(±)-1-(Benzyloxy)-6-bromo-3-(1,4-dioxaspiro[4.5]dec-8-yl)-2-oxabicyclo[2.2.2]octan-5-one

A round bottomed flask equipped with magnetic stirrer was charged with(±)-3-(benzyloxy)-6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-2-cyclohexen-1-one(78.4 g, 219 mmol) and dichloromethane (600 ml). To the stirred solutionwas added N-bromosuccinimide (40.9 g, 230 mmol) in one portion, followedby aqueous hydrobromic acid (3 drops, 48% aqueous solution). Theresulting solution was stirred at room temperature for 2 hr, then pouredinto a separating funnel containing aqueous sodium metabisulfitesolution (150 ml) and dichloromethane (200 ml). The layers wereseparated and the organic layer was washed with brine (200 ml), driedover magnesium sulfate, filtered, then concentrated in vacuo to give asolid. Trituration with methanol (500 ml) afforded the title compound(82.8 g, 86%) as a white solid. m/z (ES⁺) 437 and 439 [(1:1), M+H⁺].

Preparation 4 5-Benzyloxy)-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol

A round bottomed flask was charged with(±)-1-(benzyloxy)-6-bromo-3-(1,4-dioxaspiro[4.5]dec-8-yl)-2-oxabicyclo[2.2.2]octan-5-one(36 g, 82.4 mmol) and anhydrous N,N-dimethylformamide (300 ml). To thestirred solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (13.6 ml,90.6 mmol) in one portion before heating to 140° C. for 19 hr withvigorous stirring. The reaction mixture was allowed to cool to roomtemperature and most of the solvent was removed under reduced pressure.The remaining oil was partitioned between dichloromethane (500 ml) andwater (100 ml), and the layers were separated. The organic phase waswashed with water (2×100 ml) followed by brine (100 ml). The organicphase was dried over magnesium sulfate, filtered and concentrated invacuo to afford a brown solid. Purification via FCC (SiO₂,dichloromethane then ethyl acetate/ether, 1:9 v/v) furnished the titlecompound as white flakes (750 mg, 89%). δ_(H) (CDCl₃): 0.18 (6H, s),0.20 (6H, s), 0.97 (9H, s), 1.03 (9H, s), 1.72-1.87 (2H, m), 2.15-2.17(2H, m), 2.42-2.48 (4H, m), 3.33 (1H, tt), 6.32 (1H, d), 6.39 (1H, dd),6.94 (1H, d).

Preparation 8cis-N-Benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine

To a flask equipped with magnetic stirrer was loaded4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (3.20 g,7.36 mmol). Anhydrous 1,2-dichloroethane (85 ml) was added, followed bybenzylamine (0.97 ml, 8.83 mmol) as a solution in 1,2-dichloroethane (20ml). Activated powdered 4 Å molecular sieves (5.80 g) were added and thereaction mixture stirred vigorously for 2.5 hr.Tetramethylammoniumtriacetoxyborohydride (2.90 g, 11.0 mmol) was addedin one portion and the reaction mixture stirred for 64 hr. Aqueoussodium hydroxide solution (30 ml, 0.4M) was added and vigorous stirringwas continued for 0.5 hr. The reaction mixture was then filtered throughcelite, washing with dichloromethane (100 ml). The layers were separatedand the aqueous layer was extracted with dichloromethane (2×50 ml). Thecombined organic phases were washed with brine (100 ml), dried (MgSO₄),filtered and concentrated in vacuo affording the crude product.Purification via FCC (SiO₂, ethyl acetate/petroleum ether, gradientelution using 1:9, 1:4, then 3:7 v/v) furnished the title compound (2.69g, 70%) as a pale yellow oil. δ_(H) (CDCl₃) 0.01 (6H, s), 0.05 (6H, s),0.77 (9H, s), 0.83 (9H, s), 1.31 (1H, br), 1.39 (4H, m), 1.52 (2H, m),1.70 (2H, m), 2.69 (1H, m), 2.75 (1H, m), 6.10 (1H, d), 6.23 (1H, dd),6.84 (1H, d), 7.15 (5H, m).

Preparation 9N-Benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]amine

To a flask equipped with magnetic stirrer was added4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (817 mg,1.88 mmol). Dichloromethane (50 ml) was added followed by benzylamine(0.82 ml, 7.52 mmol) and activated 4 Å molecular sieves (10.0 g). Thereaction mixture was stirred vigorously for 15 hr, then dichloromethane(50 ml) was added and the reaction mixture filtered through celite,washing with dichloromethane (50 ml). The filtrate was concentrated invacuo affording the title compound (1.00 g, 86%) as a yellow oil. δ_(H)(CDCl₃) 0.19 (6H, s), 0.26 (6H, s), 0.98 (9H, s), 1.03 (9H, s), 1.51(1H, m), 1.72 (1H, m), 2.03 (2H, m), 2.45 (1H, m), 2.60 (1H, m), 3.04(1H, m), 3.22 (1H, m), 4.55 (1H, d), 4.60 (1H, d), 6.31 (1H, d), 6.41(1H, dd), 6.93 (1H, d), 7.33 (5H, m).

Preparation 10trans-N-Benzyl-N-[4-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine

To a flask equipped with magnetic stirrer was addedN-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]amine(4.00 g, 7.63 mmol) and tetrahydrofuran (480 ml) followed by methanol(120 ml). To the solution was added sodium borohydride (1.16 g, 30.5mmol) and the reaction mixture stirred for 17 hr. The reaction mixturewas then diluted with diethyl ether (600 ml) and aqueous sodiumhydroxide (400 ml, 0.4M) was added. After stirring for 10 min, thelayers were separated and the aqueous layer extracted withdichloromethane (3×100 ml). The combined organic phases were washed withbrine (50 ml), dried over magnesium sulfate and concentrated in vacuo.Purification via FCC (SiO₂, ethyl acetate/petroleum ether, gradientelution using 1:9, 1:4, then 3:7, v/v) furnished the title compound as acream solid (2.09 g, 54%). δ_(H) (CDCl₃) 0.01 (6H, s), 0.05 (6H, s),0.80 (9H, s), 0.85 (9H, s), 1.18 (4H, m), 1.66 (2H, m), 1.87 (2H, m),2.19 (1H, m), 2.68 (1H, M), 6.12 (1H, d), 6.23 (1H, dd), 6.77 (1H, d),7.17 (5H, m).

Preparation 11trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine

To a flask was addedtrans-N-benzyl-N-[4-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine(500 mg, 0.95 mmol) and ethanol (20 ml). To the stirred solution wasadded palladium (10% w/w on activated carbon, 200 mg, 0.19 mmol) as aslurry in ethanol (5 ml). The reaction vessel was evacuated, then placedunder hydrogen. The reaction mixture was stirred vigorously under anatmosphere of hydrogen for 18 hr, then filtered through a celite plug,washing with methanol (100 ml). The solvent was removed in vacuoaffording the title compound (402 mg, 97%) as a colourless oil. δ_(H)(CDCl₃) 0.01 (6H, s), 0.05 (6H, s), 0.78 (9H, s), 0.82 (9H, s), 1.08(2H, m), 1.21 (2H, m), 1.62 (2H, m), 1.78 (2H, m), 2.59 (2H, m), 6.11(1H, d), 6.22 (1H, dd), 6.78 (1H, d).

Preparation 12cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine

To a flask equipped with magnetic stirrer was addedcis-N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine(700 mg, 1.33 mmol) and ethanol (30 ml). To the stirred solution wasadded palladium (10% w/w on activated carbon, 283 mg, 0.27 mmol) as aslurry in ethanol (5 ml). The reaction vessel was evacuated then placedunder hydrogen. The reaction mixture was stirred vigorously under anatmosphere of hydrogen for 18 hr then filtered through a celite plug,washing with methanol (100 ml). The solvent was removed in vacuoaffording the title compound (561 mg, 97%) as a colourless oil. δ_(H)(CDCl₃) 0.01 (6H, s), 0.04 (6H, s), 0.78 (9H, s), 0.83 (9H, s),1.21-1.55 (10H, m), 2.64 (1H, m), 3.05 (1H, m), 6.11 (1H, d), 6.22 (1H,dd), 6.84 (1H, d).

Preparation 13N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]benzenesulfonamide

Method A:

To a solution of Preparation 12 (i.e.,cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine(200 mg, 459 μmol) and benzenesulfonyl chloride (71 μl, 557 μmol) in DCE(25 mL) was added NEt₃ (128 μl, 921 μmol) and DMAP (few crystals). Afterstirring for 24 hr, the reaction mixture was partitioned between CH₂Cl₂(100 ml) and H₂O (20 ml) and the aqueous layer extracted with CH₂Cl₂ (50ml). The combined organic extracts were washed with brine (50 ml) anddried (MgSO₄). Filtration and solvent evaporation gave the titlecompound (264 mg, quant) as a colourless gum; δ_(H) (CDCl₃) 0.17 (s,6H), 0.19 (s, 6H), 0.98 (s, 18H), 1.40-1.80 (m, 8H), 2.78-2.84 (m, 1H),3.58-3.62 (m, 1H), 4.68 (d, 1H), 6.28 (d, 1H), 6.43 (dd, 1H), 6.96 (d,1H), 7.49-7.60 (m, 3H), 7.90-7.94 (m, 2H).

Preparation 144-Chloro-N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]benzenesulfonamide

From Preparation 12 (65 mg, 149 μmol) and 4-chlorobenzenesulfonylchloride (39 mg, 185 μmol) following method A to give the title compound(91 mg, quant.) as colourless gum. δ_(H) (CDCl₃) 0.17 (s, 6H), 0.20 (s,6H), 0.95 (s, 18H), 1.41-1.79 (m, 8H), 2.75-2.83 (m, 1H), 3.54-3.60 (m,1H), 5.01 (d, 1H), 6.24 (d, 1H), 6.40 (dd, 1H), 6.92 (d, 1H), 7.44 (d,2H), 7.83 (d, 2H).

Preparation 153-Chloro-N-[cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-4-fluorobenzenesulfonamide

From Preparation 12 (243 mg, 558 μmol) and3-chloro-4-fluorobenzenesulfonyl chloride (148 mg, 646 μmol) followingmethod A to give the title compound (350 mg, quant.) as yellow solid.δ_(H) CDCl₃) 0.19 (s, 6H), 0.21 (s, 6H), 0.99 (m, 18H), 1.45-1.84 (m,8H), 2.79-2.87 (m, 1H), 3.80-3.85 (m, 1H), 4.83 (d, 1H), 6.26 (d, 1H),6.43 (dd, 1H), 6.92 (d, 1H), 7.28 (t, 1H), 7.77-7.83 (m, 1H), 7.97 (dd,1H).

Preparation 16N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-2-thiophenesulfonamide

From Preparation 12 (243 mg, 558 μmol) and 2-thiophenesulfonyl chloride(172 mg, 940 μmol) following method A to give the title compound (325mg, quant.) as a tan solid. δ_(H) (CDCl₃) 0.18 (s, 6H), 0.21 (s, 6H),0.96 (s, 9H), 0.98 (s, 9H), 1.42-1.84 (m, 8H), 2.77-2.84 (m, 1H),3.64-3.70 (m, 1H), 4.76 (d, 1H), 6.27 (d, 1H), 6.42 (dd, 1H), 6.94 (d,1H), 7.06 (dd, 1H), 7.56 (dd, 1H), 7.62 (dd, 1H).

Preparation 175-Chloro-N-[cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-2-thiophenesulfonamide

From Preparation 12 (243 mg, 558 μmol) and 5-chloro-2-thiophenesulfonylchloride (151 mg, 696 μmol) following method A to give the titlecompound (343 mg, quant.) as a yellow oil. δ_(H) (CDCl₃) 0.18 (s, 6H),0.22 (s, 6H), 0.95 (s, 9H), 0.99 (s, 9H), 1.40-1.84 (m, 8H), 2.78-2.85(m, 1H), 3.63-3.69 (m, 1H), 4.77 (d, 1H), 6.28 (d, 1H), 6.42 (dd, 1H),6.90 (d, 1H), 6.94 (d, 1H), 7.40 (d, 1H).

Preparation 18N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-3-nitroBenzene sulfonamide

From Preparation 12 (243 mg, 558 μmol) and 3-nitrobenzenesulfonylchloride (136 mg, 614 μmol) following method A to give the titlecompound (347 mg, quant.) as a yellow oil. δ_(H) (CDCl₃) 0.17 (s, 6H),0.21 (s, 6H), 0.96 (s, 18H), 1.42-1.79 (m, 8H), 2.77-2.84 (m, 1H),3.59-3.65 (m, 1H), 4.96 (d, 1H), 6.25 (d, 1H), 6.41 (dd, 1H), 6.93 (d,1H), 7.64 (t, 1H), 7.83 (dd, 1H), 8.13 (dd, 1H), 8.19 (d, 1H).

Preparation 19N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-4-nitrobenzenesulfonamide

From Preparation 12 (180 mg, 413 μmol) and 4-nitrobenzenesulfonylchloride (110 mg, 614 μmol) following method A to give the titlecompound (256 mg, quant.) as a yellow oil. δ_(H) (CDCl₃) 0.19 (s, 6H),0.21 (s, 6H), 0.98 (s, 18H), 1.40-1.80 (m, 8H), 2.79-2.86 (m, 1H),3.65-3.71 (m, 1H), 4.83 (d, 1H), 6.28 (d, 1H), 6.42 (dd, 1H), 6.94 (d,1H), 8.10 (d, 2H), 8.38 (d, 2H).

Preparation 20N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-2,4-dinitrobenzenesulfonamide

From Preparation 12 (60 mg, 138 μmol) and 2,4-dinitrobenzenesulfonylchloride (45 mg, 169 μmol) following method A to give the title compound(92 mg, quant.) as an orange solid. δ_(H) (CDCl₃) 0.19 (s, 6H), 0.21 (s,6H), 0.97 (s, 18H), 1.45-1.82 (m, 8H), 2.79-2.87 (m, 1H), 3.80-3.84 (brs, 1H), 5.71-5.80 (br, 1H), 6.26 (d, 1H), 6.42 (dd, 1H), 6.94 (d, 1H),8.39 (d, 1H), 8.53 (dd, 1H), 8.65 (d, 1H).

Preparation 213-Cyano-N-[cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]benzenesulfonamide

From Preparation 12 (243 mg, 558 μmol) and 3-chlorosulfonylbenzonitrile(124 mg, 615 μmol) following method A to give the title compound (335mg, quant.) as a yellow gum. δ_(H) (CDCl₃) 0.17 (s, 6H), 0.20 (s, 6H),0.98 (s, 18H), 1.41-1.79 (m, 8H), 2.77-2.83 (m, 1H), 3.59-3.64 (m, 1H),4.96 (d, 1H), 6.24 (d, 1H), 6.41 (dd, 1H), 6.94 (d, 1H), 7.63 (t, 1H),7.82 (dd, 1H), 8.14 (dd, 1H), 8.19 (d, 1H).

Preparation 22N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-4-(methylsulfonyl)benzenesulfonamide

From Preparation 12 (243 mg, 558 μmol) and4-methylsulfonylbenzenesulfonyl chloride (156 mg, 612 μmol) followingmethod A to give the title compound (365 mg, quant.) as a yellow oil.δ_(H) (CDCl₃) 0.17 (s, 6H), 0.20 (s, 6H), 0.97 (s, 18H), 1.41-1.79 (m,8H), 2.77-2.83 (m, 1H), 3.08 (s, 3H), 3.60-3.66 (m, 1H), 4.87 (d, 1H),6.27 (d, 1H), 6.41 (dd, 1H), 6.93 (d, 1H), 8.09 (s, 4H).

Preparation 23N-[trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]benzenesulfonamide

From Preparation 11 (497 mg, 1.14 mmol) and benzenesulfonyl chloride(176 μl, 1.37 mmol) following method A to give the title compound (656mg, quant.) as a yellow solid. δ_(H) (CDCl₃) 0.17 (s, 6H), 0.20 (s, 6H),1.24-1.40 (m, 4H), 1.73-1.81 (m, 2H), 1.88-1.97 (m, 2H), 2.68-2.77 (m,1H), 3.11-3.20 (m, 1H), 4.86 (d, 1H), 6.26 (d, 1H), 6.38 (dd, 1H), 6.86(d, 1H), 7.46-7.59 (m, 3H), 7.92 (d, 2H).

Preparation 24N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-2-naphthalenesulfonamide

From Preparation 12 (44 mg, 100 μmol) and 2-naphthalenesulfonyl chloride(25 mg, 110 μmol) following method A to give the title compound (63 mg,quant.) as a white solid. δ_(H) (CDCl₃) 0.17 (s, 6H), 0.20 (s, 6H), 0.96(m, 18H), 1.42-1.83 (m, 8H), 2.77-2.85 (m, 1H), 3.79-3.84 (m, 1H), 4.81(d, 1H), 6.23 (d, 1H), 6.43 (dd, 1H), 6.91 (d, 1H), 7.55-7.65 (m, 2H),7.84-8.00 (m, 4H), 8.40 (m, 1H).

Preparation 25N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-4-methylbenzenesulfonamide

From Preparation 12 (42 mg, 96 μmol) and 4-toluenesulfonyl chloride (37mg, 194 μmol) following method A to give the title compound (57 mg,quant.) as a white solid. δ_(H) (CDCl₃) 0.17 (s, 6H), 0.19 (s, 6H), 0.96(s, 18H), 1.43-1.78 (m, 8H), 2.40 (s, 3H), 2.74-2.81 (m, 1H), 3.51-3.58(m, 1H), 5.03 (d, 1H), 6.25 (d, 1H), 6.38 (dd, 1H), 6.92 (d, 1H), 7.28(d, 2H), 7.79 (d, 2H).

Preparation 26N-[trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-4-methylbenzenesulfonamide

From Preparation 11 (44 mg, 100 μmol) and 4-toluenesulfonyl chloride (22mg, 115 μmol) following method A to give the title compound (59 mg,quant.) as a yellow oil. δ_(H) (CDCl₆) 0.16 (s, 6H), 0.19 (s, 6H), 0.95(s, 9H), 0.98 (s, 9H), 1.20-1.39 (m, 4H), 1.73-1.80 (m, 2H), 1.90-1.97(m, 2H), 2.42 (s, 3H), 2.67-2.78 (m, 1H), 3.09-3.20 (m, 1H), 4.41 (d,1H), 6.26 (d, 1H), 6.37 (dd, 1H), 6.86 (d, 1H), 7.30 (d, 2H), 7.78 (d,2H).

Preparation 27N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-4-methoxybenzenesulfonamide

From Preparation 12 (42 mg, 96 μmol) and 4-methoxybenzenesulfonylchloride (46 mg, 222 μmol) following method A to give the title compound(58 mg, quant.) as a white solid. δ_(H) (CDCl₃) 0.20 (s, 12H), 1.00 (s,18H), 1.40-1.81 (m, 8H), 2.77-2.84 (m, 1H), 3.52-3.59 (br s, 1H), 3.89(s, 3H), 4.92 (d, 1H), 6.29 (d, 1H), 6.42 (dd, 1H), 6.96 (d, 1H), 7.33(d, 2H), 7.80 (d, 2H).

Preparation 28N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-5-dimethyl-amino)-1-naphthalenesulfonamide

From Preparation 12 (44 mg, 100 μmol) and dansyl chloride (30 mg, 110μmol) following method A to give the title compound (67 mg, quant.) as ayellow solid. δ_(H) (CDCl₃) 0.16 (s, 6H), 0.20 (s, 6H), 0.95 (m, 18H),1.45-1.86 (m, 8H), 2.75-2.83 (m, 1H), 3.02 (s, 6H), 3.50-3.55 (m, 1H),4.75 (d, 1H), 6.20 (d, 1H), 6.40 (dd, 1H), 6.62 (d, 1H), 7.30 (d, 1H),7.58-7.65 (m, 2H), 8.21 (d, 1H), 8.50 (d, 1H), 8.57 (d, 1H).

Preparation 29N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-1-methyl-1H-imidazole-4-sulfonamide

From Preparation 12 (42 mg, 96 μmol) and1-methyl-4-chlorosulfonylimidazole (35 mg, 193 μmol) following method Ato give the title compound (56 mg, quant.) as a pale yellow oil. δ_(H)(CDCl₃) 0.17 (s, 6H), 0.19 (s, 6H), 0.95 (s, 9H), 0.97 (s, 9H),1.48-1.66 (m, 6H), 1.79-1.88 (m, 2H), 2.75-2.82 (m, 1H), 3.54-3.59 (m,1H), 3.73 (s, 3H), 5.06 (d, 1H), 6.25 (d, 1H), 6.40 (dd, 1H), 6.96 (d,1H), 7.44 (s, 1H), 7.47 (s, 1H).

Preparation 30N-[cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-5-(3-isoxazolyl)-2-thiophenesulfonamide

From Preparation 12 (42 mg, 96 μmol) and5-(3-isoxazolyl)-2-thiophenesulfonyl chloride (48 mg, 192 μmol)following method A (62 mg, quant.) as a yellow oil. δ_(H) (CDCl₃)0.17-0.18 (m, 12H), 0.95-0.97 (m, 18H), 1.51-1.89 (m, 8H), 2.77-2.83 (m,1H), 3.48-3.55 (m, 1H), 5.20 (d, 1H), 6.27 (d, 1H), 6.39 (dd, 1H), 6.49(d, 1H), 6.97 (d, 1H), 7.42 (d, 1H), 7.60 (d, 1H), 8.29 (d, 1H).

Preparation 31 Methyl3-({[cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amino}sulfonyl)benzoate

From Preparation 12 (0.80 g, 1.8 mmol) and methyl3-chlorosulfonylbenzoate (0.48 g, 2.0 mmol) following method A (i-Pr₂NEtemployed instead of NEt₃) to give the title compound (1.09 g, 94%) as anoff-white solid. δ_(H) (CDCl₃) 0.17 (s, 6H), 0.19 (s, 6H), 0.96 (s,18H), 1.41-1.78 (m, 8H), 2.73-2.82 (m, 1H), 3.58-3.62 (m, 1H), 3.94 (s,3H), 5.09 (d, 2H), 6.23 (d, 1H), 6.38 (dd, 1H), 6.92 (d, 1H), 7.60 (t,1H), 8.09 (dd, 1H), 8.22 (dd, 1H), 8.57 (dd, 1H).

Preparation 32 Methyl4-({[cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amino}sulfonyl)benzoate

From Preparation 12 (217 mg, 498 μmol) and methyl4-chlorosulfonylbenzoate (132 mg, 562 μmol) following method A (i-Pr₂NEtused instead of NEt₃) to give the title compound (295 mg, 93%) as anoff-white solid. δ_(H) (CDCl₃) 0.17 (s, 6H), 0.19 (s, 6H), 0.96 (s,18H), 1.40-1.76 (m, 8H), 2.75-2.83 (m, 1H), 3.59-3.64 (m, 1H), 3.95 (s,3H), 5.28 (d, 2H), 6.25 (d, 1H), 6.37 (dd, 1H), 6.91 (d, 1H), 7.99 (d,2H), 8.16 (d, 2H).

Preparation 334-Cyano-N-[trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]benzenesulfonamide

From Preparation 11 (350 mg, 803 μmol) and 4-chlorosulfonylbenzonitrile(200 mg, 992 μmol) following method A to give the title compound (482mg, quant.) as an off-white solid. m/z (ES⁻) 618 [M+OH]⁻.

Preparation 34

N-[2-Chloro-4-({[cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amino}sulfonyl)phenyl]acetamide

From Preparation 12 (67 mg, 154 μmol) and4-acetamido-3-chlorobenzenesulfonyl chloride (64 mg, 239 μmol) followingmethod A (solvent system employed=DCE-THF, 7:1) to give the titlecompound (103 mg, quant.) as a white solid. δ_(H) (CDCl₃) 0.18 (s, 6H),0.21 (s, 6H), 0.98 (m, 18H), 1.42-1.80 (m, 8H), 2.24 (s, 3H), 2.76-2.82(m, 1H), 3.54-3.60 (m, 1H), 5.03 (d, 1H), 6.24 (d, 1H), 6.39 (dd, 1H),6.92 (d, 1H), 7.79 (d, 1H), 7.93 (s, 1H), 8.60 (d, 1H).

Preparation 35N-[trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-4-fluorobenzenesulfonamide

From Preparation 11 (350 mg, 803 μmol) and 4-fluorobenzenesulfonylchloride (190 mg, 970 μmol) following method A to give the titlecompound (477 mg, quant.) as an off-white solid. m/z (ES⁻) 593 [M−H]⁻.

Preparation 36N-[trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-2,4-difluorobenzenesulfonamide

From Preparation 11 (350 mg, 803 μmol) and 2,4-difluorobenzenesulfonylchloride (210 mg, 970 μmol) following method A to give the titlecompound (450 mg, 92%) as an off-white solid. m/z (ES⁻) 611 [M−H]⁻.

Preparation 37N-[trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-2,3,4,5,6-pentafluorobenzenesulfonamide

From Preparation 11 (350 mg, 803 μmol) and pentafluorobenzenesulfonylchloride (140 μL, 970 μmol) following method A to give the titlecompound (450 mg, 84%) as an off-white solid. m/z (ES⁻) 664 [M−H]⁻.

Preparation 38N-[trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-3-(trifluoromethyl)benzenesulfonamide

From Preparation 11 (350 mg, 803 μmol) and3-trifluoromethylbenzenesulfonyl chloride (160 μL, 970 μmol) followingmethod A to give the title compound (516 mg, quant.) as an off-whitesolid; m/z (ES⁻) 642 [M−H]⁻.

Example 1 N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]benzenesulfonamide

Method B:

Preparation 13 (264 mg, 459 μmol) was dissolved in DCE (50 ml) andtreated with H₂O (17 ml) and TFA (17 ml). The mixture was heated undergentle reflux for 24 hr and after cooling, toluene (70 ml) added. Thesolvents were removed under reduced pressure and MeOH (50 ml) added.Following solvent evaporation, a brown oil was isolated which wassubjected to FCC (PE-EtOAc, 3:1 to 1:1) to furnish the title compound(102 mg, 64%) as a white solid. δ_(H) (CD₃OD) 1.48-1.76 (m, 8H),2.73-2.80 (m, 1H), 3.40-3.44 (m, 1H), 6.22-6.26 (m, 2H), 6.95 (d, 1H),7.5-7.62 (m, 3H), 7.91 (d, 2H); m/z (ES⁻) 346 [M−H]⁻.

Example 24-Chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide

From Preparation 14 (91 mg, 149 μmol) following method B to give thetitle compound (29 mg, 51%) as a white solid. δ_(H) ((CD₃)₂CO) 1.52-1.81(m, 8H), 2.79-2.90 (m, 1H), 3.51-3.59 (m, 1H), 6.28 (dd, 1H), 6.35 (d,1H), 6.70 (d, 1H), 6.97 (d, 1H), 7.63 (d, 2H), 7.88 (s, 1H), 7.91 (d,2H), 7.99 (s, 1H); m/z (ES) 382 [M+H]⁺.

Example 33-Chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]-4-fluorobenzenesulfonamide

From Preparation 15 (350 mg, 557 μmol) following method B to give thetitle compound (178 mg, 80%) as an off-white solid. δ_(H) (CD₃OD)1.58-1.82 (m, 8H), 2.78-2.85 (m, 1H), 3.48-3.52 (br s, 1H), 6.26-6.31(m, 2H), 6.98 (d, 1H), 7.46 (t, 1H), 7.88-7.93 (m, 1H), 8.06 (dd, 1H);m/z (ES⁻) 398 [M−H]⁻.

Example 4N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2-thiophenesulfonamide

From Preparation 16 (325 mg, 558 μmol) following method B to give thetitle compound (151 mg, 77%) as a white solid. SH (CD₃OD) 1.59-1.87 (m,8H), 2.79-2.88 (m, 1H), 3.56-3.59 (m, 1H), 6.23-6.25 (m, 2H), 6.99 (d,1H), 7.17 (dd, 1H), 7.66 (dd, 1H), 7.79 (dd, 1H); m/z (ES⁻) 352 [M−H]⁻.

Example 55-Chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]-2-thiophenesulfonamide

From Preparation 17 (343 mg, 556 μmol) following method B to give thetitle compound (153 mg, 71%) as white solid. δ_(H) (CD₃OD) 1.60-1.88 (m,8H), 2.80-2.88 (m, 1H), 3.56-3.59 (br s, 1H), 6.23-6.25 (m, 2H), 6.99(d, 1H), 7.10 (d, 1H), 7.48 (d, 1H); m/z (ES⁻) 386 [M−H]⁻.

Example 6N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-nitrobenzenesulfonamide

From Preparation 18 (347 mg, 558 μmol) following method B to give thetitle compound (114 mg, 51%) as a yellow solid. H (CD₃OD) 1.59-1.90 (m,8H), 2.79-2.86 (m, 1H), 3.55-3.58 (br s, 1H), 6.25-6.30 (m, 2H), 6.98(d, 1H), 7.85 (t, 1H), 8.32 (d, 1H), 8.50 (d, 1H), 8.77 (s, 1H); m/z(ES⁻) 391 [M−H]⁻.

Example 7N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-nitrobenzenesulfonamide

From Preparation 19 (256 mg, 413 μmol) following method B to give thetitle compound (119 mg, 74%) as a white solid. 4 (CD₃OD) 1.55-1.80 (m,8H), 2.78-2.86 (m, 1H), 3.53-3.59.(m, 1H), 6.21-6.29 (m, 2H), 6.97 (d,1H), 8.16 (d, 2H), 8.41 (d, 2H); m/z (ES⁻) 391 [M−H]⁻.

Example 8N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2,4-dinitrobenzenesulfoilamide

From Preparation 20 (92 mg, 138 μmol) following method B to give thetitle compound (26 mg, 43%) as a pale yellow solid. 41 (CD₃OD) 1.58-1.86(m, 8H), 2.79-2.86 (m, 1H), 3.76-3.80 (br s, 1H), 6.25-6.30 (m, 2H),6.99 (d, 1H), 8.41 (d, 1H), 8.64 (dd, 1H), 8.75 (d, 1H); m/z (ES⁻) 436[M−H]⁻.

Example 93-Cyano-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide

From Preparation 21 (335 mg, 558 μmol) following method B to give thetitle compound (110 mg, 53%) as a white solid. δ_(H) (CD₃OD) 1.59-1.81(m, 8H), 2.79-2.85 (m, 1H), 3.51-3.56 (br s, 1H), 6.26-6.30 (m, 2H),6.98 (d, 1H), 7.79 (t, 1H), 8.00 (d, 1H), 8.21 (d, 1H), 8.29 (s, 1H);m/z (ES⁻) 371 [M−H]⁻.

Example 10N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-(methylsulfonyl)benzenesulfonamide

From Preparation 22 (365 mg, 558 μmol) following method B to give thetitle compound (158 mg, 66%) as a white solid. δ_(H) (CD₃OD) 1.51-1.77(m, 8H), 2.72-2.81 (m, 1H), 3.17 (s, 3H), 3.49-3.52 (br s, 1H),6.20-6.24 (m, 2H), 6.93 (d, 1H), 8.12 (s, 4H); m/z (ES⁻) 424 [M−H]⁻.

Example 11 N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]benzenesulfonamide

From Preparation 23 (656 mg, 1.14 mmol) following method B to give thetitle compound (310 mg, 78%) as a white solid. δ_(H) (CD₃OD) 1.32-1.43(m, 4H), 1.74-1.88 (m, 4H), 2.68-2.77 (m, 1H), 3.05-3.17 (m, 1H),6.20-6.27 (m, 2H), 6.85 (d, 1H), 7.56-7.66 (m, 3H), 7.92 (d, 2H); m/z(ES⁻) 346 [M−]⁻.

Example 12N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2-naphthalenesulfonamide

Method C:

Preparation 24 (63 mg, 100 μmol) was dissolved in CH₂Cl₂ (6 ml) andtreated with H₂O (2 ml) and TFA (3 ml). After stirring for 18 hr, thereaction mixture was treated with toluene (30 ml). The solvents wereremoved under reduced pressure and MeOH (15 ml) added. Following solventevaporation, a brown gum was obtained which was subjected to FCC(PE-EtOAc, 3:1 to 1:1) to afford the title compound (30 mg, 75%) as awhite solid. δ_(H) (CD₃OD) 1.49-1.78 (m, 8H), 2.70-2.79 (m, 1H),3.44-3.48 (br s, 1H), 6.21-6.24 (m, 2H), 6.94 (d, 1H), 7.60-7.68 (m,2H), 7.91 (dd, 1H), 7.95-7.99 (m, 1H), 8.02-8.06 (m, 2H), 8.44 (d, 1H);m/z (ES⁺) 398 [M+H]⁺.

Example 13N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-methylbenzenesulfonamide

From Preparation 25 (57 mg, 96 μmol) following method C to give thetitle compound (21 mg, 60%) as a white solid. δ_(H) (CD₃OD) 1.51-1.82(m, 8H), 2.46 (s, 3H), 2.76-2.83 (m, 1H), 3.41 (br s, 1H), 6.26-6.30 (m,2H), 6.98 (d, 1H), 7.40 (d, 2H), 7.81 (d, 2H); m/z (ES⁻) 360 [M−H]⁻.

Example 14N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-methylbenzenesulfonamide

From Preparation 26 (59 mg, 100 μmol) following method C to give thetitle compound (10 mg, 28%) as a white solid. δ_(H) (CD₃OD) 1.33-1.42(m, 4H), 1.75-1.84 (m, 4H), 2.47 (s, 3H), 2.67-2.77 (m, 1H), 3.02-3.11(m, 1H), 6.21-6.28 (m, 2H), 6.85 (d, 1H), 7.41 (d, 2H), 7.80 (d, 2H);m/z (ES⁻) 360 [M−H]⁻.

Example 15N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-methoxybenzenesulfonamide

From Preparation 27 (58 mg, 96 μmol) following method C to give thetitle compound (21 mg (58%) as a white solid. δ_(H) (CD₃OD) 1.55-1.82(m, 8H), 2.77-2.83 (m, 1H), 3.42 (br s, 1H), 3.91 (s, 3H), 6.27-6.30 (m,2H), 6.98 (d, 1H), 7.08 (d, 2H), 7.83 (d, 2H); m/z (ES⁺) 378 [M+H]⁺.

Example 16N-[cis-4-2,4-Dihydroxyphenyl)cyclohexyl]-5-(dimethylamino)-1-naphthalenesulfonamide

From Preparation 28 (67 mg, 100 μmol) following method C to give thetitle compound (20 mg, 45%) as an off-white solid. δ_(H) (CD₃OD)1.35-1.70 (m, 8H), 2.68-2.77 (m, 1H), 3.48-3.52 (m, 1H), 6.19-6.23 (m,2H), 6.62 (d, 1H), 7.33 (d, 1H), 7.59 (t, 1H), 7.64 (t, 1H), 8.25 (d,1H), 8.53 (d, 1H), 8.58 (d, 1H); m/z (ES⁺)=441 [M+H]⁺.

Example 17N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-methyl-1H-imidazole-4-sulfonamide

From Preparation 29 (56 mg, 96 μmol) following method C to give thetitle compound (21 mg, 58%) as a white solid. δ_(H) (CD₃OD) 1.59-1.88(m, 8H), 2.78-2.85 (m, 1H), 3.58 (br s, 1H), 3.83 (s, 3H), 6.26-6.30 (m,2H), 6.99 (d, 1H), 7.78 (s, 1H), 7.83 (s, 1H); m/z (ES⁺) 352 [M+H]⁺.

Example 18N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-5-(3-isoxazolyl)-2-thiophenesulfonamide

From Preparation 30 (62 mg, 96 μmol) following method C to give thetitle compound (15 mg, 38%) as a pale orange solid. δ_(H) (CD₃OD)1.59-1.96 (m, 8H), 2.79-2.87 (m, 1H), 3.59-3.66 (br s, 1H), 6.25-6.32(m, 2H), 6.82 (d, 1H), 6.99 (d, 1H), 7.63 (d, 1H), 7.68 (d, 1H), 8.49(d, 1H); m/z (ES⁻) 419 [M−H]⁻.

Example 19 Methyl3-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoate

Method D:

To a stirred solution of Preparation 31 (196 mg, 309 μmol) in THF (14ml) was added HOAc (64 μl, 1116 μmol) and TBAF.H₂ O (324 mg, 1239 μmol).After 30 min, H₂O (30 ml) and EtOAc (30 ml) were added and stirringcontinued for 10 min. The layers were separated, and the aqueous phaseextracted with EtOAc (2×20 ml). The combined organic extracts werewashed with brine (30 ml) and dried (MgSO₄). Filtration andconcentration under reduced pressure furnished a yellow gum that waspurified by FCC (PE-EtOAc, 4:1 to 2:3) to yield the title compound (110mg, 88%) as a white solid. δ_(H) ((CD₃)₂CO) 1.53-1.82 (m, 8H), 2.80-2.90(m, 1H), 3.54-3.61 (m, 1H), 3.94 (s, 3H), 6.28 (dd, 1H), 6.35 (d, 1H),6.81 (d, 1H), 6.97 (d, 1H), 7.75 (t, 1H), 7.88 (s, 1H), 7.98 (s, 1H),8.14 (dd, 1H), 8.22 (dd, 1H), 8.50 (dd, 1H); m/z (ES⁻) 404 [M−H]⁻.

Example 20 Methyl4-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoate

From Preparation 32 (295 mg, 465 μmol) following method D to give thetitle compound (142 mg, 75%) as a white solid. δ_(H) ((CD₃)₂CO)1.51-1.80 (m, 8H), 2.80-2.88 (m, 1H), 3.55-3.61 (br, 1H), 3.93 (s, 3H),6.28 (dd, 1H), 6.35 (d, 1H), 6.81 (d, 1H), 6.97 (d, 1H), 7.88 (s, 1H),7.98 (s, 1H), 8.02 (d, 2H), 8.18 (d, 2H); m/z (ES⁻) 404 [M−H]⁻.

Example 21 Methyl3-({[trans-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoate

Method E:

A solution of Preparation 11 (150 mg, 344 μmol) and methyl3-chlorosulfonylbenzoate (97 mg, 414 μmol) in DCE (5 ml) was treatedwith NEt₃ (98 μl, 700 μmol) and DMAP (few crystals) and stirred for 18hr. The reaction mixture was partitioned between CH₂Cl₂ (100 ml) and H₂O(20 ml), and the aqueous layer extracted with CH₂Cl₂ (50 ml). Thecombined organic extracts were washed with brine (50 ml), dried (MgSO₄),filtered and concentrated in vacuo. The resulting oil was dissolved inTHF (10 ml) and treated with HOAc (100 μl) and TBAF.H₂O (360 mg, 1380μmol). After 30 min, H₂O (30 ml) and EtOAc (30 ml) were added, andstirring continued for a further 10 min. The layers were separated, andthe aqueous phase was extracted with EtOAc (2×20 ml) before the combinedorganic extracts were washed with brine (30 ml) and dried (MgSO₄).Filtration and concentration under reduced pressure furnished the crudeproduct which was purified by FCC (PE-EtOAc, 4:1 to 2:3) to yield thetitle compound (110 mg, 78%) as a white solid. δ_(H) (CD₃OD) 1.24-1.41(m, 4H), 1.63-1.81 (m, 4H), 2.62-2.73 (m, 1H), 3.05-3.17 (m, 1H), 3.94(s, 3H), 6.16-6.23 (m, 2H), 6.80 (d, 1H), 7.68 (t, 1H), 8.10 (d, 1H),8.21 (d, 1H), 8.49 (s, 1H); m/z (ES⁻) 404 [M−H]⁻.

Example 22 Methyl4-({[trans-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoate

From Preparation 11 (150 mg, 344 μmol) and methyl4-chlorosulfonylbenzoate (97 mg, 414 μmol) following method E to givethe title compound (110 mg, 78%) as a white solid. δ_(H) (CD₃OD)1.20-1.41 (m, 4H), 1.70-1.81 (m, 4H), 2.61-2.70 (m, 1H), 3.04-3.18 (m,1H), 3.92 (s, 3H), 6.15-6.22 (m, 2H), 6.69 (d, 1H), 7.98 (d, 2H), 8.16(d, 2H); m/z (ES⁺) 406 [M+H]⁺.

Example 234-Cyano-N-[trans-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide

From Preparation 33 (482 mg, 803 μmol) following method D to give thetitle compound (210 mg, 70%) as a white solid. δ_(H) ((CD₃)₂SO)1.28-1.42 (m, 4H), 1.61-1.89 (m, 4H), 2.55-2.63 (m, 1H), 3.04-3.18 (br,1H), 3.22 (d, 1H), 6.17 (dd, 1H), 6.27 (d, 1H), 6.80 (d, 1H), 8.04 (d,2H), 8.18 (d, 2H), 8.97 (s, 1H), 9.03 (s, 1H); m/z (ES⁻) 371 [M−H]⁻.

Example 24N-[2-Chloro-4-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)phenyl]acetamide

From Preparation 34 (103 mg, 154 μmol) following method D to give thetitle compound (37 mg, 55%) as a white solid. δ_(H) ((CD₃)₂CO) 1.55-1.81(m, 8H), 2.23 (s, 3H), 2.80-2.88 (m, 1H), 3.51-3.58 (m, 1H), 6.28 (dd,1H), 6.35 (d, 1H), 6.66 (d, 1H), 6.96 (d, 1H), 7.82 (dd, 1H), 7.89 (brs, 1H), 7.92 (d, 1H), 7.99 (br s, 1H), 8.49 (d, 1H), 8.85 (br s, 1H);m/z (ES⁺) 439 [M+H]⁺.

Example 254-Amino-3-chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide

From Preparation 34 (103 mg, 154 μmol) following method B to give thetitle compound (30 mg, 49%) as a white solid. δ_(H) ((CD₃)₂CO) 1.52-1.63(m, 4H), 1.67-1.80 (m, 4H), 2.79-2.86 (m, 1H), 3.41-3.49 (m, 1H), 5.67(br s, 2H), 6.29-6.35 (m, 3H), 6.94-6.99 (m, 2H), 7.55 (dd, 1H), 7.72(d, 1H), 7.88 (br s, 1H), 7.97 (br s, 1H); δ_(c) (CD₃OD)=27.0, 31.3,35.6, 48.9, 102.2, 106.2, 114.3, 117.2, 124.8, 126.8, 126.9, 128.4,128.6, 148.4, 155.0, 155.7; m/z (ES⁺) 397 [M+H]⁺.

Example 264-Acetyl-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide

From Preparation 12 (150 mg, 344 μmol) and 4′-chlorosulfonylacetophenone(90 mg, 412 μmol) following method E to give the title compound (77 mg,56%) as a white solid. δ_(H) (CD₃OD) 1.50-1.76 (m, 8H), 2.63 (s, 3H),2.72-2.80 (m, 1H), 3.44-3.50 (m, 1H), 6.21-6.25 (m, 2H), 6.93 (d, 1H),8.00 (d, 2H), 8.13 (d, 2H); m/z (ES⁻) 388 [M−H]⁻.

Example 27N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-(trifluoromethoxy)benzenesulfonamide

From Preparation 12 (150 mg, 344 μmol) and4-trifluoromethoxybenzenesulfonyl chloride (109 mg, 418 μmol) followingmethod E to give the title compound (110 mg, 76%) as a white solid.δ_(H) (CD₃OD) 1.52-1.77 (m, 8H), 2.72-2.81 (m, 1H), 3.43-3.48 (m, 1H),6.21-6.25 (m, 2H), 6.94 (d, 1H), 7.46 (d, 2H), 8.00 (d, 2H); m/z (ES⁻)430 [M−H]⁻.

Example 28N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-fluorobenzenesulfonamide

From Preparation 35 (477 mg, 803 μmol) following method D to give thetitle compound (170 mg, 58%) as a white solid. δ_(H) ((CD₃)₂SO)1.20-1.38 (m, 4H), 1.59-1.77 (m, 4H), 2.52-2.60 (m, 1H), 2.91-3.01 (br,1H), 6.08 (dd, 1H), 6.19 (d, 1H), 6.73 (d, 1H), 7.37-7.44 (m, 2H), 7.70(d, 1H), 7.83-7.90 (m, 2H), 8.86 (s, 1H), 8.97 (s, 1H); m/z (ES⁻) 364[M−H]⁻.

Example 29N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2,4-difluorobenzenesulfonamide

From Preparation 36 (450 mg, 739 μmol) following method D to give thetitle compound (180 mg, 64%) as a white solid. δ_(H) (CD₃)₂SO) 1.20-1.39(m, 4H), 1.57-1.72 (m, 4H), 2.52-2.60 (m, 1H), 3.00-3.11 (br, 1H), 6.18(dd, 1H), 6.40 (d, 1H), 6.74 (d, 1H), 7.25 (m, 1H), 7.52 (m, 1H), 7.88(m, 1H), 8.01 (d, 1H), 8.86 (s, 1H), 8.98 (s, 1H); m/z (ES⁻) 382 [M−H]⁻.

Example 30N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2,3,4,5,6-pentafluorobenzenesulfonamide

From Preparation 37 (450 mg, 675 μmol) following method D to give thetitle compound (207 mg, 70%) as a white solid. δ_(H) (CD₃)₂SO) 1.27-1.41(m, 4H), 1.60-1.83 (m, 4H), 2.54-2.61 (m, 1H), 3.16-3.25 (m, 1H), 6.09(dd, 1H), 6.21 (d, 1H), 6.78 (d, 1H), 8.75 (d, 1H), 8.85 (s, 1H), 8.99(s, 1H); m/z (ES⁻) 436 [M−H]⁻.

Example 31N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-(trifluoromethyl)benzenesulfonamide

From Preparation 38 (516 mg, 801 μmol) following method D to give thetitle compound (240 mg, 72%) as a white solid. δ_(H) 5 ((CD₃)₂SO)1.22-1.41 (m, 4H), 1.60-1.79 (m, 4H), 2.52-2.62 (m, 1H), 3.01-3.14 (br,1H), 6.13 (dd, 1H), 6.25 (d, 1H), 6.79 (d, 1H), 7.89 (t, 1H), 7.97 (d,1H), 8.06 (d, 1H), 8.13-8.20 (m, 2H), 8.91 (s, 1H), 9.02 (s, 1H); m/z(ES−) 414 [M−H]⁻.

Example 32N-[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3,5-bis(trifluoromethyl)benzenesulfonamide

From Preparation 11 (200 mg, 459 μmol) and3,5-bis(trifluoromethyl)benzene sulfonyl chloride (172 mg, 550 μmol)following method E to give the title compound (128 mg, 58%) as a whitesolid. δ_(H) <((CD₃)₂SO) 1.20-1.38 (m, 4H), 1.56-1.72 (m, 4H), 2.52-2.60(m, 1H), 3.06-3.18 (br, 1H), 6.08 (dd, 1H), 6.39 (d, 1H), 6.72 (d, 1H),8.10-8.16 (br, 1H), 8.39 (s, 2H), 8.44 (s, 1H), 8.84 (s, 1H), 8.97 (s,1H); m/z (ES⁻) 482 [M−H]⁻.

Example 33N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl](phenyl)methanesulfonamide

From Preparation 12 (150 mg, 344 μmol) and4-trifluoromethoxybenzenesulfonyl chloride (109 mg, 418 μmol) followingmethod E to give the title compound (50 mg, 39%) as a white solid. δ_(H)(CD₃OD) 1.59-1.75 (m, 6H), 1.81-1.90 (m, 2H), 2.77-2.83 (m, 1H),3.53-3.58 (br s, 1H), 4.36 (s, 2H), 6.23-6.28 (m, 2H), 6.95 (d, 1H),7.34-7.40 (m, 3H), 7.43-7.48 (m, 2H); m/z (ES⁻) 360 [M−H]⁻.

Example 342-Chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]-5-(trifluoromethyl)benzenesulfonamide

Method F:

2-Chloro-5-trifluoromethylbenzenesulfonyl chloride (39 mg, 140 μmol) andDMAP (several crystals) were added to a stirred suspension ofPreparation 12 (50 mg, 115 mol) and morpholinomethyl polystyrene (85 mgof 3.4 μmol mg⁻¹ resin) in CH₂Cl₂ (4 ml), and the mixture was shaken for24 hr. Polymer-bound tris(2-aminoethyl)amine (50 mg of 3.5 μmol mg⁻¹resin) and NEt₃ (32 μl, 228 μmol) were added, and the reaction mixtureagitated for 5 days. Filtration, washing with CH₂Cl₂, and solventevaporation under reduced pressure gave the crude product, which wasdissolved in MeOH (4 ml). The resulting solution was added topolymer-supported fluoride (200 mg of ca. 3 μmol mg⁻¹ resin), and themixture was shaken at 20° C. for 4 days, before being filtered through ashort SiO₂ pad. After washing with MeOH and HCl in Et₂O (2 M, 1 ml), thecombined solutions were concentrated in vacuo to give the title compound(15 mg, 29%) as a white solid. δ_(H) (CD₃OD) 1.54-1.85 (m, 8H),2.75-2.84 (m, 1H), 3.57-3.63 (br s, 1H), 6.24-6.29 (m, 2H), 6.97 (m,1H), 7.84 (d, 1H), 7.91 (dd, 1H), 8.34 (d, 1H); m/z (ES⁻)448 [M−H]⁻.

Example 353,5-Dichloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]benzenesulfonamide

From Preparation 12 (50 mg, 115 μmol) and 3,5-dichlorobenzenesulfonylchloride (34 mg, 138 μmol) following method F to give the title compound(9 mg, 19%) as a white solid. δ_(H) (CD₃OD) 1.60-1.81 (m, 8H), 2.80-2.88(m, 1H), 3.55 (s, 1H), 6.28-6.33 (m, 2H), 6.99 (d, 1H), 7.77 (t, 1H),7.91 (d, 2H); m/z (ES⁻) 414 [M−H]⁻.

Example 364-Bromo-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]-2,5-difluorobenzenesulfonamide

From Preparation 12 (50 mg, 115 μmol) and4-bromo-2,5-difluorobenzenesulfonyl chloride (41 mg, 141 μmol) followingmethod F to give the title compound (21 mg, 41%) as a white solid. δ_(H)(CD₃OD) 1.56-1.80 (m, 8H), 2.73-2.81 (m, 1H), 3.59 (s, 1H), 6.21-6.26(m, 2H), 6.94 (d, 1H), 7.67-7.74(m, 2H); m/z (ES⁻) 461 [M−H]⁻.

Example 37N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3,5-bis(trifluoromethyl)benzenesulfonamide

From Preparation 12 (50 mg, 115 μmol) and3,5-bis(trifluoromethyl)benzenesulfonyl chloride (43 mg, 138 μmol)following method F to give the title compound (15 mg, 27%) as a whitesolid. δ_(H) (CD₃OD) 1.59-1.82 (m, 8H), 2.80-2.90 (m, 1H), 3.54 (s, 1H),6.27-6.32 (m, 2H), 6.97 (d, 1H), 8.30 (s, 1H), 8.51 (s, 2H); m/z (ES⁻)482 [M−H]⁻.

Example 38N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-naphthalenesulfonamide

From Preparation 12 (50 mg, 115 μmol) and 1-naphthalenesulfonyl chloride(31 mg, 137 μmol) following method F to give the title compound (17 mg,37%) as a white solid. δ_(H) (CD₃OD) 1.31-1.72 (m, 8H), 2.68-2.78 (m,1H), 3.51 (s, 1H), 6.20-6.26 (m, 2H), 6.71 (d, 1H), 7.60-7.80 (m, 3H),8.07 (d, 1H), 8.19 (d, 1H), 8.29 (dd, 1H), 8.87 (d, 1H); m/z (ES⁺) 398[M+H]⁺.

Example 39N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-(hydroxymethyl)benzenesulfonamide

Method G:

A solution of LiAIH₄ in THF (1M, 520 μl) was treated with a solution ofExample 19 (20 mg, 49 μmol) in THF (8 ml). After 45 min, the reactionmixture was partitioned between aqueous HCl (1M, 15 ml) and EtOAc (15ml). The aqueous phase was extracted with EtOAc (15 mL) and the combinedorganic extracts washed with aqueous NaHCO₃ (saturated, 15 ml), brine(15 ml), before being dried (MgSO₄). Filtration and solvent evaporationin vacuo provided the title compound (19 mg, quant.) as a white solid.δ_(H) ((CD₃)₂CO) 1.51-1.62 (m, 4H), 1.68-1.81 (m, 4H), 2.78-2.84 (m,1H), 3.49-3.53 (m, 1H), 4.47 (t, 1H), 4.73 (d, 2H), 6.28 (dd, 1H), 6.35(d, 1H), 6.57 (d, 1H), 6.98 (d, 1H), 7.50-7.60 (m, 2H), 7.78 (d, 1H),7.90 (s, 1H), 7.93 (s, 1H), 8.00 (s, 1H); m/z (ES⁺) 378 [M+H]⁺.

Example 40N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-4-(hydroxymethyl)benzenesulfonamide

From Example 20 (16 mg, 40 μmol) following method G to give the titlecompound (11 mg, 73%) as a white solid. δ_(H) ((CD₃)₂CO)=1.52-1.63 (m,4H), 1.66-1.80 (m, 4H), 2.78-2.84 (m, 1H), 3.48-3.54 (m, 1H), 4.34 (t,1H), 4.73 (d, 2H), 6.28 (dd, 1H), 6.35 (d, 1H), 6.53 (d, 1H), 6.98 (d,1H), 7.56 (d, 2H), 7.84-7.89 (m, 3H), 7.98 (s, 1H); m/z (ES⁺) 378[M+H]⁺.

Example 414-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic acid

Method H:

A solution of Example 20 (18 mg, 44 μmol) in THF-MeOH (3:1, 4 mL) wastreated with a solution of LiOH.H₂O (12 mg, 286 μmol) in H₂O (2 ml).After stirring for 40 min, aqueous HCl (1 M, 500 μl) was added, and themixture partitioned between H₂O (5 ml) and EtOAc (10 ml). The aqueousphase was extracted with EtOAc (5 ml) and the combined organic extractswere washed with brine (7 ml) and dried (MgSO₄). Filtration and solventevaporation followed by RP-HPLC afforded the title compound (13 mg, 75%)as a white solid. δ_(H) ((CD₃)₂CO) 1.47-1.80 (m, 8H), 2.77-2.86 (m, 1H),3.52-3.60 (m, 1H), 6.27 (dd, 1H), 6.34 (d, 1H), 6.76 (d, 1H), 6.96 (d,1H), 8.00 (d, 2H), 8.20 (d, 2H); m/z (ES⁻) 390 [M−H]⁻.

Example 423-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic acid

From Example 19 (107 mg, 264 μmol) following method H to give the titlecompound (50 mg, 48%) as a white solid. δ_(H) ((CD₃)₂CO) 1.54-1.82 (m,8H), 2.79-2.88 (m, 1H), 3.53-3.61 (m, 1H), 6.28 (dd, 1H), 6.35 (d, 1H),6.80 (d, 1H), 6.97 (d, 1H), 7.75 (t, 1H), 7.84-8.08 (br, 2H), 8.14 (d,1H), 8.25 (d, 1H), 8.55 (s, 1H); m/z (ES⁺) 392 [M+H]⁺.

Example 434-({[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic acid

From Example 22 (100 mg, 247 μmol) following method H to give the titlecompound (48 mg, 50%) as a white solid. δ_(H) (CD₃OD) 1.28-1.44 (m, 4H),1.71-1.82 (m, 4H), 2.64-2.72 (m, 1H), 3.06-3.16 (m, 1H), 6.16-6.24 (m,2H), 6.81 (d, 1H), 7.97 (d, 2H), 8.17 (d, 2H); m/z (ES⁺) 392 [M+H]⁺.

Example 443-({[trans-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoic acid

From Example 21 (100 mg, 247 μmol) following method H to give the titlecompound (46 mg, 47%) as a white solid. δ_(H) (CD₃OD) 1.30-1.48 (m, 4H),1.75-1.90 (m, 4H), 2.68-2.77 (brs, 1H), 3.10-3.19 (m, 1H), 6.21-6.29 (m,2H), 6.85 (d, 1H), 7.71 (t, 1H), 8.11 (d, 1H), 8.27 (d, 1H), 8.56 (s,1H); m/z (ES⁺) 392 [M+H]⁺.

Example 45 Benzyl(2S)-2-{[3-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoyl]amino}-3-phenylpropanoate

Method I:

A solution of Example 42 (28 mg, 72 μmol) in DMF (1 ml) was treated witha solution of L-PheOBn-HOTs (35 mg, 82 μmol) in DMF (1.5 ml) andi-Pr₂NEt (45 μl, 258 μmol) before being cooled to 0° C. A solution ofHATU (34 mg, 89 μmol) in DMF (1.5 ml) was added, and the reactionmixture allowed to warm to 20° C. over 3 days. Following concentrationin vacuo, the residue was partitioned between EtOAc (10 ml) and H₂O (10ml). The aqueous phase was extracted with EtOAc (5 ml) and the combinedorganic extracts were washed with aqueous HCl (2M, 2×15 ml), H₂O (15ml), aqueous NaHCO₃ (saturated, 2×15 ml), and brine (15 ml), beforebeing dried (MgSO₄). Filtration and solvent evaporation gave the crudeproduct which was purified by RP-HPLC to give the title compound (13 mg,29%) as a white solid. δ_(H) ((CD₃)₂CO) 1.51-1.63 (m, 4H), 1.66-1.80 (m,4H), 2.79-2.85 (m, 1H), 3.15-3.22 (m, 1H), 3.28-3.35 (m, 1H), 3.49-3.55(m, 1H), 4.94-5.01 (m, 1H), 5.16-5.19 (m, 2H), 6.29 (dd, 1H), 6.35 (d,1H), 6.71 (d, 1H), 6.97 (d, 1H), 7.18-7.37 (m, 10H), 7.67 (t, 1H), 7.89(s, 1H), 8.00 (s, 1H), 8.02-8.06 (m, 2H), 8.25 (d, 1H), 8.33 (s, 1H);m/z (ES⁻) 627 [M−H]⁻.

Example 46(2S)-2-{[3-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoyl]amino}-3-phenylpropanoicacid

Method J:

A suspension of Example 45 (5.1 mg, 8.1 μmol) and Pd (10% on C, 5.6 mg)in i-PrOH (3 ml) was placed under a H₂ atmosphere, and stirred at 20° C.After 3 days, EtOAc (10 ml) was added and the mixture was filteredthrough Celite, subsequently washing with EtOAc (10 ml). Solventevaporation in vacuo provided the title compound (4.0 mg, 91%) as awhite solid. δ_(H) ((CD₃)₂CO) 1.51-1.63 (m, 4H), 1.68-1.80 (m, 4H),2.78-2.85 (m, 1H), 3.15-3.20 (m, 1H), 3.34-3.40 (m, 1H), 3.49-3.58 (m,1H), 4.90-4.99 (m, 1H), 6.28 (dd, 1H), 6.35 (d, 1H), 6.71 (d, 1H), 6.97(d, 1H), 7.19 (t, 1H), 7.27 (t, 2H), 7.35 (d, 2H), 7.66 (t, 1H),7.85-7.91 (m, 2H), 8.03 (s, 1H), 8.05 (s, 1H), 8.10 (d, 1H), 8.33 (s,1H); m/z (ES⁻) 538 [M−H]⁻.

Example 47 Benzyl3-{[3-({[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoyl]amino}propanoate

From Example 42 (43 mg, 110 μmol) and β-AlaOBn.HOTs (43 mg, 121 μmol)following method I to give the title compound (8 mg, 13%) as a whitesolid. δ_(H) ((CD₃)₂CO) 1.53-1.64 (m, 4H), 1.70-1.80 (m, 4H), 2.75 (t,2H), 2.78-2.84 (m, 1H), 3.50-3.57 (m, 1H), 3.69-3.74 (m, 2H), 5.13 (s,2H), 6.28 (dd, 1H), 6.35 (d, 1H), 6.71 (d, 1H), 6.96 (d, 1H), 7.27-7.39(m, 5H), 7.67 (t, 1H), 7.91 (s, 1H), 8.01-8.16 (m, 4H), 8.37 (s, 1H);m/z (ES⁻) 551 [M−H]⁻.

Example 48N-[3-({[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]amino}sulfonyl)benzoyl]-β-alanine

From Example 47 (9.3 mg, 16.8 μmol) following method J to give the titlecompound (5.6 mg, 72%) as a white solid. δ_(H) ((CD₃)₂CO) 1.51-1.65 (m,4H), 1.69-1.79 (m, 4H), 2.68 (t, 2H), 2.77-2.83 (m, 1H), 3.50-3.57 (m,1H), 3.63-3.70 (m, 2H), 6.28 (dd, 1H), 6.35 (d, 1H), 6.70 (d, 1H), 6.97(d, 1H), 7.68 (t, 1H), 7.80-7.95 (br, 1H), 8.02-8.12 (m, 3H), 8.37 (s,1H); m/z (ES⁻) 461 [M−H]⁻.

Example 49N-[cis-4-(2,4-Dihydroxyphenyocyclohexyl]-4-(hydrazinocarbonyl)benzenesulfonamide

A solution of Example 20 (16 mg, 39 μmol) and N₂H₄.H₂O (79 μl, 1624μmol) in MeOH-EtOH (1:4, 2.5 ml) was heated under reflux for 24 hr. Oncooling to 20° C., MeOH (15 ml) was added and the solution filtered.Solvent evaporation furnished the title compound (16 mg, quant) as awhite solid. δ_(H) (CD₃OD) 1.56-1.80 (m, 8H), 2.77-2.83 (m, 1H),3.46-3.52 (m, 1H), 6.26-6.30 (m, 2H), 6.98 (m, 1H), 7.98 (d, 2H), 8.02(d, 2H); m/z (ES⁺) 406 [M+H]⁺.

Example 50N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-(1H-tetrazol-5-yl)benzenesulfonamide

A solution of Example 9 (20 mg, 54 μmol) in DMF (2 ml) was treated withNH₄Cl (17 mg, 323 μmol) and NaN₃ (21 mg, 323 μmol). The mixture washeated under reflux for 6 hr, then stirred for 18 hr at 20° C., beforebeing partitioned between EtOAc (30 ml) and H₂O (5 ml). The aqueousphase was extracted with EtOAc (3×15 ml) and the combined organicextracts were washed with brine (30 ml) and dried (MgSO₄). Filtration,solvent evaporation under reduced pressure, and FCC (EtOH-EtOAc, 1:3)afforded the title compound (16 mg, 72%) as a pale yellow solid. δ_(H)((CD₃)₂CO) 1.30-1.88 (m, 8H), 2.60-2.71 (m, 1H), 3.62-3.69 (m, 1H),4.23-4.30 (m, 1H), 6.20 (dd, 1H), 6.44 (d, 1H), 6.50 (d, 1H), 6.87 (d,1H), 7.55 (t, 1H), 7.63-7.68 (m, 1H), 7.72-7.76 (m, 1H), 7.80 (d, 1H),8.30 (d, 1H), 8.73 (s, 1H); m/z (ES⁻) 414 [M−H]⁻.

All patents, patent applications, and publications cited above areincorporated herein by reference in their entirety.

The present invention is not to be limited in scope by the specificembodiments described herein, which are intended as single illustrationsof individual aspects of the invention, and functionally equivalentmethods and components are within the scope of the invention. Indeed,various modifications of the invention, in addition to those shown anddescribed herein will become apparent to those skilled in the art fromthe foregoing description. Such modifications are intended to fallwithin the scope of the appended claims.

1-34. (canceled)
 35. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: R is a(C₃-C₈)cycloalkyl ring substituted by one of —N(R¹)SO₂(CHR¹)_(n)R² or—(C₁-C₆)alkylN(R¹)SO₂(CHR¹)_(n)R², wherein each R¹ is independentlyselected from hydrogen, (C₁-C₆)alkyl, phenyl and benzyl; R² is aryl,heteroaryl or heterocycloalkyl optionally substituted with one or moresubstituents independently selected from halogen, OH, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, trifluoromethoxy, —S(O)_(m)(C₁-C₆)alkyl, amino,—N(R¹)CO(C₁-C₆)alkyl, COOR¹, —(C₁-C₆)alkylCOOR¹, —CO(C₁-C₆)alkyl,—(C₁-C₆)alkylOH, —(C₁-C₆)alkylamino, di-((C₁-C₆)alkyl)amino, nitro,cyano, —CONH(CHR¹)_(n)CO₂R¹, —CONR¹N(R¹)₂, trifluoromethyl, aryl,heteroaryl, and heterocycloalkyl; n is an integer from 0 to 6; and m isan integer from 0 to
 2. 36. A compound of claim 35, wherein R is acyclohexyl ring which is substituted at the 3- or 4-position.
 37. Acompound of claim 36, wherein R is a cyclohexyl ring which issubstituted at the 4-position.
 38. A compound of claim 35, wherein R isa cyclopentyl ring which is substituted at the 3-position.
 39. Acompound of claim 35, wherein R is substituted by—(C₁-C₆)alkylN(R¹)SO₂(CHR¹)_(n)R².
 40. A compound of claim 35, wherein Ris substituted by —N(R¹)SO₂(CHR¹)_(n)R².
 41. A compound selected fromthe group consisting of:N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2-thiophenesulfonamide;5-Chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]-2-thiophenesulfonamide;N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-methyl-1H-imidazole-4-sulfonamide;N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-5-(3-isoxazolyl)-2-thiophenesulfonamide;and a pharmaceutically acceptable salt thereof.
 42. A pharmaceuticalcomposition for lightening skin or reducing the pigmentation of skin ina human, comprising a pharmaceutically acceptable carrier, and askin-lightening or pigmentation-reducing amount of a compound of formulaI:

or a pharmaceutically acceptable salt thereof, wherein: R is a(C₃-C₈)cycloalkyl ring substituted by one of —N(R¹)SO₂(CHR¹)_(n)R² or—(C₁-C₆)alkylN(R¹)SO₂(CHR¹)_(n)R², wherein each R¹ is independentlyselected from hydrogen, (C₁-C₆)alkyl, phenyl and benzyl; R² is aryl,heteroaryl or heterocycloalkyl optionally substituted with one or moresubstituents independently selected from halogen, OH, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, trifluoromethoxy, —S(O)_(m)(C₁-C₆)alkyl, amino,—N(R¹)CO(C₁-C₆)alkyl, COOR¹, —(C₁-C₆)alkylCOOR¹, —CO(C₁-C₆)alkyl,—(C₁-C₆)alkylOH, —(C₁-C₆)alkylamino, di-((C₁-C₆)alkyl)amino, nitro,cyano, —CONH(CHR¹)_(n)CO₂R¹, —CONR¹N(R¹)₂, trifluoromethyl, aryl,heteroaryl, and heterocycloalkyl; n is an integer from 0 to 6; and m isan integer from 0 to
 2. 43. A pharmaceutical composition of claim 42,wherein R is a cyclohexyl ring which is substituted at the 3- or4-position.
 44. A pharmaceutical composition of claim 43, wherein R is acyclohexyl ring which is substituted at the 4-position.
 45. Apharmaceutical composition of claim 42, wherein R is a cyclopentyl ringwhich is substituted at the 3-position.
 46. A pharmaceutical compositionof claim 42, wherein R is substituted by one of—(C₁-C₆)alkylN(R¹)SO₂(CHR¹)_(n)R².
 47. A pharmaceutical composition ofclaim 42, wherein R is substituted by one of —N(R¹)SO₂(CHR¹)_(n)R². 48.A pharmaceutical composition for lightening skin or reducing thepigmentation of skin in a human, comprising a pharmaceuticallyacceptable carrier, and a skin-lightening or pigmentation-reducingamount of a compound selected from the group consisting of:N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2-thiophenesulfonamide;5-Chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]-2-thiophenesulfonamide;N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-methyl-1H-imidazole-4-sulfonamide;N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-5-(3-isoxazolyl)-2-thiophenesulfonamide;and a pharmaceutically acceptable salt thereof.
 49. A pharmaceuticalcomposition of claim 43, wherein the skin-lightening orpigmentation-reducing effective amount of the compound of formula I orpharmaceutically acceptable salt thereof is an amount that is effectiveat inhibiting tyrosinase in a human.
 50. A method of lightening skin ina human, comprising administering to said human a skin-lighteningeffective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: R is a(C₃-C₈)cycloalkyl ring or substituted by one of —N(R¹)SO₂(CHR¹)_(n)R² or—(C₁-C₆)alkylN(R¹)SO₂(CHR¹)_(n)R², wherein each R¹ is independentlyselected from hydrogen, (C₁-C₆)alkyl, phenyl and benzyl; R² is aryl,heteroaryl or heterocycloalkyl optionally substituted with one or moresubstituents independently selected from halogen, OH, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, trifluoromethoxy, —S(O)_(m)(C₁-C₆)alkyl, amino,—N(R¹)CO(C₁-C₆)alkyl, COOR¹, —(C₁-C₆)alkylCOOR¹, —CO(C₁-C₆)alkyl,—(C₁-C₆)alkylOH, —(C₁-C₆)alkylamino, di-((C₁-C₆)alkyl)amino, nitro,cyano, —CONH(CHR¹)_(n)CO₂R¹, —CONR¹N(R¹)₂, trifluoromethyl, aryl,heteroaryl, and heterocycloalkyl; n is an integer from 0 to 6; and m isan integer from 0 to
 2. 51. The method of claim 50, wherein R is acyclohexyl ring which is substituted at the 3- or 4-position.
 52. Themethod of claim 50, wherein R is a cyclohexyl ring which is substitutedat the 4-position.
 53. The method of claim 50, wherein R is acyclopentyl ring which is substituted at the 3-position.
 54. The methodof claim 50, wherein R is substituted by one of—(C₁-C₆)alkylN(R¹)SO₂(CHR¹)_(n)R².
 55. The method of claim 50, wherein Ris substituted by one of —N(R¹)SO₂(CHR¹)_(n)R².
 56. A method oflightening skin in a human, comprising administering to said human askin-lightening effective amount of a compound selected from the groupconsisting of:N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-2-thiophenesulfonamide;5-Chloro-N-[cis-4-(2,4-dihydroxyphenyl)cyclohexyl]-2-thiophenesulfonamide;N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-methyl-1H-imidazole-4-sulfonamide;N-[cis-4-(2,4-Dihydroxyphenyl)cyclohexyl]-5-(3-isoxazolyl)-2-thiophenesulfonamide;and a pharmaceutically acceptable salt thereof.
 57. The method of claim50, wherein the skin-lightening effective amount of the compound offormula I or pharmaceutically acceptable salt thereof is an amount thatis effective at inhibiting tyrosinase in a human.
 58. The method ofclaim 50, wherein the compound of formula I, or a pharmaceuticallyacceptable salt thereof, is applied topically.